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.     

Microwave promoted synthesis of cycl[3.2.2]azines in water via a new three-component reaction

A microwave-promoted and base-catalyzed synthesis of cycl[3.2.2]azines is accomplished in water via a three-component reaction (3-CR) of 2-picoline, α-bromoacetophenone and alkyne. The extension of the methodology to the synthesis of steroidal and carbocyclic cycl[3.2.2]azine is also reported.     

Synthesis of decahydropyrrolo[2,1,5-cd]indolizine derivatives through RuCl3/AgOTf induced alkene–alkene and alkene–arene double cycloisomerizations

In the presence of RuCl₃/AgOTf, pyrrolizidine derivative with styrenyl substituents at the 3,5-positions undergo a 6-exo-trig cyclization and subsequent intramolecular Friedel–Crafts reactions to form decahydropyrrolo[2,1,5-cd]indolizine or decahydrocycl[3.2.2]azine derivatives. The cycloisomerization is highly stereoselective. Presence of electron donating groups on the styrenyl substituents inhibits the double cycloisomerization process and results in a trans to cis epimerization instead. No reaction takes place when electron withdrawing groups are present on the styrenyl substituents. Possible mechanisms are proposed for the observed reactions.     

2-Azacycl[3.2.2] azine. Polyhalogenation and nucleophilic displacement reactions

1,4-Dibromo-2-azacycl[3.2.2] azine (2) when treated with methanolic sodium methoxide affords the I-methoxy-4-bromo derivative (3). Perchloro-2-azacycl[3.2.2]azine (7) was prepared and treated with methanolic sodium methoxide to yield the 5-methoxy (8) and 5,7-dimethoxy (9) derivatives as major products, depending upon reaction conditions. Catalytic removal of the chlorine substituents of compounds 8 and 9 afforded the 5-methoxy (10) and 5,7-dimethoxy (11) derivatives. Treatment of compound 2 with butyllithium affords the I-butyl derivative (5) of 2-azacycl[3.2.2]azine, while treatment with zinc in acetic acid yields 4-bromo-2-azacycl[3.2.2]azine (6). 4-Formyl-2-azacycl[3.2.2]azine (12) when treated with phosphorus pentachloride affords the 1,3-dichloro-4-formyl derivative 13. Possible rationals for the nucleophilic displacement are given.     

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.     

The synthesis of 1,4-diazacycl[3,2,2]azine

The diazaanalog of “cycl[3,2,2]azine”, “1,4-diazacycl[3,2,2]azine” (1,4,7b-triazacyclopent-[cd]indene) and its 2-methyl derivative were prepared. These compounds are subject to facile acid-catalyzed hydrolysis affording substituted imidazo[1,2-a]pyridines.     

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.     

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.     

Synthesis of 2-methylthioindolizine-3-carbonitriles using nitro ketene dithioacetal

The reaction of 1-cyanomethylpyridinium chloride or bromide, 1a-i , with 1,1-bis(methylthio)-2-nitroethylene ( 2 ) in the presence of triethylamine as a base in ethanol gave the corresponding 2-methylthioindolizine-3-carbonitrile 3 and 2-methyl-thio-1-nitroindolizine-3-carbonitrile 4 in good yields, respectively. Compounds 3a,f were key intermediates for the synthesis of cycl[3.2.2]azine derivatives.     

4-甲基吡咯并[2,1,5-cd]中氮茚的合成

以2-乙基吡啶生成的叶立德为原料,采用1,3-偶极环加成反应,得到了一系列3-乙酰基(或苯甲酰基)-5-乙基中氮茚衍生物,后者与KOH在加热条件下发生分子内缩合,得到了一系列4-甲基吡咯并[2,1,5-cd]中氮茚.     

Synthesis and reactivity of 5-Br(I)-indolizines and their parallel cross-coupling reactions

Poorly available 5-iodo- and 5-bromoindolizines were prepared via regioselective lithiation of indolizines followed by halogenation. 5-Halogenoindolizines were found to be passive toward nucleophiles, whereas they may be trifluoroacetylated at C-3 and involved in reaction with DMAD giving cycl[3.2.2]azine. The first successful Suzuki-coupling of 5-bromo(iodo)indolizines with different arylboronic acids (performed as a parallel synthesis) led to a series of 5-arylindolizines; the effect of substituents on the reaction yield was examined.     

Stereoselective transformation of indole diazabicyclo[3.2.2]nonedione to azepinoindole

[reaction: see text] The synthesis of an indole diazabicyclo[3.2.2]nonedione derivative was achieved in a few steps starting from L-tryptophan. Reduction with borane-THF complex leads to fragmentation of the bicycle and the stereoselective formation of an azepinoindole derivative was observed.     

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.     

Cyclazines and topological resonance energies

The resonance energies and magnetic properties of cyclazines such as pyrido[2,1,6-cd]quinolizine ( 1 ) and pyrido[2,1,5-de]quinolizine ( 6 ) were calculated by means of Aihara's TRE. Consequently, cycl[3.2.2]azines and cycl[3.3.3]azines were predicted to be aromatic, while cycl[4.3.2]azines were predicted to be anti-aromatic.     

2,3,3-trimethyl-3h-pyrrolo[3,2-c]quinolines and polymethine dyes based on them

2,3,3-Trimethyl-3H-pyrrolo[3,2-c]quinoline and its 8-methoxy derivative were obtained from methyl isopropyl ketone 4-quinolylhydrazones. These bases form quaternary salts at the azine nitrogen atom, from which polymethine dyes were obtained. The changes in the absorption spectra of the dyes in solutions with various acidities were examined.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 948–951, July, 1982.     

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.     

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.     

Bleach/acetic acid-promoted chlorinative ring expansion of [2.2.1]- and [2.2.2]-bicycles

[formula: see text] Treatment of vinyl-substituted [2.2.1]- and [2.2.2]-bicyclocarbinols with NaOCl and AcOH provides [3.2.1]- and [3.2.2]-beta-chloro-bicycloketones, respectively. For [2.2.2]-bicycles, these chlorinative ring expansions are particularly efficient and selective.     

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.     

Synthesis of a novel 8-thia-1,4-diazacycl[3.3.2] azine

A unique covalently hydrated cyclazine adduct, 2-imino-6a-hydroxy-4,5,6,6a-tetrahydro-7H-8-thia-J, 4-diazacycl[3.3.2]azin-5-one hydrochloride was prepared by reacting ethyl 4-chloro-acetoacetate with 4,6-diamino-2-thiopyrimidine in neutral alcohol. Neutralization gave 2-imino-5,6a-dihydroxy-6,6a-dihydro-7H-8-thia-1,4-diazacycl[3.3.2]azine which decomposed to 4,6-diamino-2-acetonylthiopyrimidine upon heating in water. Warming the hydrated hydrochloride in concentrated hydrochloric acid caused dehydration to yield 2-imino-5-hydroxy-6H-8-thia-1,4-diazacycl[3.3.2]azine hydrochloride. Partial isomerization (20%) to 2-imino-5-hydroxy-7H-8-thia-1,4-diazacycl[3.3.2]azine hydrochloride occurred during recrystallization from aqueous acidic methanol. The free base, 2-imino-5-hydroxy-7H-8-thia-1,4-diazacycl[3.3.2]azine was obtained after neutralizing either of the tautomeric hydrochlorides. Treating the free base with trifluoroacetic acid produced a mixture of the trifluoroacetate salts of the two tautomeric bases. Isomerization of one trifluoroacetate salt into the other in trifluoroacetic acid was observed by pmr at room temperature. Both 2-amino-5-hydroxy-7-nitroso-8-thia-1,4-diazacycl[3.3.2]azine and 2-amino-5-hydroxy-6-nitroso-8-thia-1,4-diazacycl[3.3.2]azine were isolated after nitrosation of the hydrochloride mixture.