Preparation of novel bicyclic piperazines by reduction of bicyclo[4.2.2]diketopiperazines: rearrangement involving 1,2-bond migration

Reduction of (1R,6R)-7,9-diazabicyclo[4.2.2]dec-3-ene-8,10-dione (5) with lithium aluminum hydride gave a mixture of the expected (1R,6R)-7,9-diazabicyclo[4.2.2]dec-3-ene (2) as well as 7,9-diazabicyclo[4.3.1]dec-3-ene (3), resulting from 1,2-σ (C-C) migration of the pendant cis-2-butenyl ring. More of the rearranged product was observed in polar solvents and upon the addition of HMPA. The relief of ring strain imparted by the olefin may promote this rearrangement, as it was not observed when the olefin was reduced prior to the reduction.     

Purine and pyrimidine derivatives from the South China Sea gorgonian Subergorgia suberosa

Three new purine derivatives, namely, 4-caryboxy-5,6-dihydro-4H,8H-pyrimido[1,2,3-cd]purine-8,10(9H)-dione (1), 7,9-dihydro-1-(3-oxobutyl)-1H-purine-6,8-dione (2), and 7-hydro-9-(3-oxobutyl)-1H-purine-6,8-dione (3) together with six known purine and pyrimidine derivatives were isolated from the EtOH/CH(2)Cl(2) extracts of the South China Sea gorgonian Subergorgia suberosa. The structures of 1-3 were determined on the bases of extensive spectroscopic analysis, including 1D and 2D NMR data.     

4-Oxoheptanedioic acid: an orthogonal linker for solid-phase synthesis of base-sensitive oligonucleotides

l,6-Dioxaspiro[4,4]nonane-2,7-dione has been found to react readily with alcohols in the presence of 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU). The 4-oxoheptanedioic acid tether obtained bears (l) a free carboxy group, which enables anchoring to aminoalkylated resins, and (2) a 4-oxobutanoate structural motif, which allows release of the target alcohol by a mild hydrazinium acetate treatment. To demonstrate the applicability of the procedure, nucleosides have been derivatized with this simple difunctional linker arm, anchored to a solid phase and subjected to synthesis and subsequent release of oligonucleotides bearing a base-sensitive biodegradable phosphate protection.     

Highly efficient racemisation of a key intermediate of the antibiotic moxifloxacin

N-Chlorination by sodium dichloroisocyanurate and dehydrochlorination by TEA, followed by hydrogenation, allowed (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane to be quantitatively racemised and the resulting trans-free cis racemate to be recycled into the resolution process to yield (1S,6R)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane, a key intermediate of moxifloxacin.     

Rigid Scaffolds: Synthesis of 2,6-Bridged Piperazines with Functional Groups in all three Bridges

The activity of pharmacologically active compounds can be increased by presenting a drug in a defined conformation, which fits exactly into the binding pocket of its target. Herein, the piperazine scaffold was conformationally restricted by substituted C₂- or C₃-bridges across the 2- and 6-position. At first, a three-step, one-pot procedure was developed to obtain reproducibly piperazine-2,6-diones with various substituents at the N-atoms in high yields. Three strategies for bridging of piperazine-2,6-diones were pursued: 1. The bicyclic mixed ketals 8-benzyl-6-ethoxy-3-(4-methoxybenzyl)-6-(trimethylsilyloxy)-3,8-diazabicyclo[3.2.1]octane-2,4-diones were prepared by Dieckmann analogous cyclization of 2-(3,5-dioxopiperazin-2-yl)acetates. 2. Stepwise allylation, hydroboration and oxidation of piperazine-2,6-diones led to 3-(3,5-dioxopiperazin-2-yl)propionaldehydes. Whereas reaction of such an aldehyde with base provided the bicyclic alcohol 9-benzyl-6-hydroxy-3-(4-methoxybenzyl)-3,9-diazabicyclo[3.3.1]nonane-2,4-dione in only 10 % yield, the corresponding sulfinylimines reacted with base to give N-(2,4-dioxo-3,9-diazabicyclo[3.3.1]nonan-6-yl)-2-methylpropane-2-sulfinamides in >66 % yield. 3. Transformation of a piperazine-2,6-dione with 1,4-dibromobut-2-ene and 3-halo-2-halomethylprop-1-enes provided 3,8-diazabicyclo[3.2.1]octane-2,4-dione and 3,9-diazabicyclo[3.3.1]nonane-2,4-dione with a vinyl group at the C₂- or a methylene group at the C₃-bridge, respectively. Since bridging via sulfinylimines and the one-pot bridging with 3-bromo-2-bromomethylprop-1-ene gave promising yields, these strategies will be exploited for the synthesis of novel receptor ligands bearing various substituents in a defined orientation at the carbon bridge     

Reaction of perfluoro-2-methylpent-2-ene with ethylenediamine and hexamethylenediamine

Reaction of perfluoro-2-methylpent-2-ene with ethylenediamine and hexamethylenediamine results in 9-fluoro-5,9-bis(pentafluoroethyl)-6,8,8-tris(trifluoromethyl)-1,4-diazabicyclo[5.2.0]nona-4,6-diene, whose structure was confirmed by X-ray analysis, and 11-pentafluoroethyl-10-trifluoromethyl-1,8-diazabicyclo[7.2.0]undeca-8,10-diene, respectively. The reaction pathways are discussed. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1578–1582, August, 1999.     

Diazobicycloalkanes with bridgehead nitrogen atoms in nodal positions. 22. Conformational analysis of benzodiazabicycloalkenes. Iterative evaluation of spectral and thermodynamic parameters

¹H and ¹³C NMR were used to investigate the conformational equilibrium of benzo[f]-1,5-diazabicyclo[3,2.2]nonene and benzo[g]-1,6-diazabicyclo[4.2.2]decene in solution at temperatures from 20 to–110C. Benzo[f]-1,5-diazabicyclo[3.2.2]nonene in this temperature interval undergoes rapid conformational exchange, while the conformation ratio changes from 7327 to 5545. The thermodynamic characteristics of this equilibrium were obtained and some NMR parameters of the individual conformers were estimated. For benzo[g]-1,6-diazabicyclo-[4.2.2]decene it was possible to attain conditions of slow exchange between two conformations whose proportion in the temperature interval studied were almost identical. The kinetics of conformational exchange were investigated and the energy of activation of the process was found to equal 42.3 kJ/mole.For Communication 21 see [1].Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1402–1407, October, 1991.     

Facile Preparation of 3,7-Diazabicyclo[3.3.0]octane and 3,7,10-Triheterocyclic [3.3.3]Propellane Ring Systems from 1,5-Diazacyclooctane 3,7-Derivatives(1)

The cyclodimerization of p-toluenesulfonamide and 3-chloro-2-(chloromethyl)-1-propene to prepare N,N'-bis(p-toluenesulfonyl)-3,7-bis(methylene)-1,5-diazacyclooctane (1a) and its ozonation to the corresponding 3,7-dione 2a are reported. Unusual transannular cyclizations initiated by lithium aluminum hydride treatment or bromination of 1a and oxidative coupling of the dioxime derived from 2a are described. These reactions lead, respectively, to the following derivatives of the little-studied 3,7-diazabicyclo[3.3.0]octane ring system: 1,5-dimethyl-3,7-diazabicyclo[3.3.0]octane (5), N,N'-bis(p-toluenesulfonyl)-1,5-bis(bromomethyl)-3,7-diazabicyclo[3.3.0]octane (8), and N,N'-bis(p-toluenesulfonyl)-1,5-dinitro-3,7-diazabicyclo[3.3.0]octane, (12). Acid-catalyzed hydration of 1a, in contrast, gives the expected 5-methyl-3,7-diazabicyclo[3.3.1]nonan-1-ol (10). Reaction of the dibromide 8 with the nucleophiles, sodium sulfide, sodium oxide, and sodium p-toluenesulfonamide conveniently delivers the corresponding novel 3,7,10-triheterocyclic [3.3.3]propellanes.     

The synthesis of proximal-benzolumazine,proxirnal-benzoxanthine,proximal-benzotheophylline and proximal-benzocaffeine

The synthesis of pyrazino[2,3-f]quinazolin-8,10-(7H,9H)dione(proximal-benzolumazine, 1 ), imidazo[4,5-f]-quinazolin-7,9-(6H,8H)-dione (proximal-benzoxanthine, 2 ), 6,8-dimethylimidazo[4,5-f]-quinazolin-7,9-(6H,8H) dione (proximal-benzotheophylline, 3 ), and 1,6,8-trimethylimidazo[4,5-f]quinazolin-7,9-(6H,8H)dione (proximal-benzocaffeine, 4 ) is reported by commencing with 2-amino-6-chlorobenzamide and proceeding via a variety of 5,6-disubstituted-2,4-(1H,3H)quinazolinediones. Methylation of 3 is shown to yield 3,6,8-trimethylimidazo[4,5-f]quinazolin-7,9-(6H,8H)dione ( 15 ) and 4 in a ratio of 4:1.     

Enantioselective microbial reduction of 6-oxo-8-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-8-azaspiro[4.5]decane-7,9-dione

The enantioselective microbial reduction of 6-oxo-8-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-8-azaspiro[4.5]decane-7,9-dione 1 to either of the corresponding (R)- or (S)-6-hydroxy-8-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-8-azaspiro[4.5]decane-7,9-diones 2 and 3 is described.     

Synthesis of regioisomeric difluoro- and 8-chloro-9- fluorobenz [g] isoquinoline-5,10-diones and SNAr displacements studies by diamines: bis(aminoalkyl)aminobenz[g] isoquinoline-5,10-diones

Convenient pathways have been developed for the synthesis of 6,7−, 6,8-, 7,9- and 8,9-difluorobenz[g] isoquinoline-5,10-diones and 8-chloro-9-fluorobenz [g] isoquinoline-5,10-dione. The crucial step in these synthesis involved the Ni-catalyzed coupling of the difluoro- or chlorofluorobenzylic zinc bromides with ethyl 3-chloroisonicotinate or ethyl 4-chloronicotinate. The reactions of the 6,7- or 8,9-difluoro regioisomers with N,N-dimethylethylenediamine led to quaternary salts which were formed by intramolecular displacements from the initial mono displacement products. These cyclizations could be obviated with the use of 3-dimethylaminopropylamine in the displacements which led to the desired bis (aminoalkyl) amino substitution products. Treatment of 8-chloro-9-fluorobenz [g] isoquinoline-5,10-dione with N,N-dimethylethylenediamine led to the regioselective displacement of fluoride. Treatment of this mono substitution product with excess N,N-dimethylethylenediamine led only to the intramolecular cyclization product which was also obtained by reaction of 8,9-difluorobenz[g] isoquinoline-9,10-dione with N,N-dimethylethylenediamine. The 6,8- and 7,9-difluoro analogues on treatment with N,N-dimethylethylenediamine or 3-dimethylaminopropylamine led to the expected bis substitution products.     

Synthesis of bridged heterocycles from <Emphasis Type="Italic">cis</Emphasis>-pyrrolidine-2,4-dicarboxylic acids: I. 3,6-Diazabicyclo[3.2.1]octanes

cis-5-Arylpyrrolidine-2,4-dicarboxylic acid monoamides undergo thermal intramolecular condensation with formation of bicyclic imides having a 3,6-diazabicyclo[3.2.1]octane skeleton. The use of copper(I) cyanide as catalyst ensures high yields of 3,6-diazabicyclo[3.2.1]octane-2,4-diones substituted at the 3-, 5-, 6-, and 7-positions. (1R*,5R*,7S*)-7-(4-Chlorophenyl)-5,6-dimethyl-3,6-diazabicyclo[3.2.1]octane-2,4-dione was found to inhibit thrombin in a buffer solution at a millimolar concentration.     

Thermal Isomerization of 7,8-Diazabicyclo[4.2.2]deca-2,4,7,9-tetraene N-oxide to Benzaldehyde Oxime

Thermal transformation of 7,8-diazabicyclo[4.2.2]deca-2,4,7,9-tetraene N-oxide ( 3 ) was observed, (Z)-benzaldehyde oxime being the major product, with (E)-benzaldehyde oxime as a minor product. N-Oxide 3 was labeled with deuterium α to the oxidized N-atom. The location of the deuterium label in the thermolysis products fitted one of two reasonable mechanisms.     

Synthesis of substituted methyl 5,5-polymethylene-2,4-dioxotetrahydropyran-3-carboxylates

Dimethyl 2-(1-bromocyclohexylcarbonyl)-, 2-(1-bromocyclopentylcarbonyl)-, and 2-(1-bromocyclobutylcarbonyl)-2-methylmalonates reacted with zinc and aromatic aldehydes to give the corresponding methyl 1-aryl-4-methyl-3,5-dioxo-2-oxaspiro[5.5]undecane-4-, 6-aryl-9-methyl-8,10-dioxo-7-oxaspiro[4.5]-decane-9-, and 5-aryl-8-methyl-7,9-dioxo-6-oxaspiro[3.5]nonane-8-carboxylates.     

NMR studies of buspirone (an anxiolytic drug) analogues

Conformations of piperazine rings in 8-{4-[4-(2-pyrimidyl)-1-piperazinyl]butyl}-8-azaspiro[4.5]-decane-7,9-dione (buspir-one — 1) and its two analogues 8-{4-[4-(2-quinolinyl)-1-piperazinyl]butyl}-8-azaspiro[4.5]-decane-7,9-dione (kaspar — 2) and 4,4-dimethyl-1-{4-[4-(2-quinolinyl)-1-piperazinyl]butyl}-2,6-piperidinedione (mesmar — 3) (Fig. 1) have been studied with the aid of ¹H NMR and ¹³C NMR spectra. For free bases the two bands corresponding to piperazine hydrogen atoms in the spectra broaden considerably with a decrease in temperature to divide into four separate bands, indicating the presence of a dynamic exchange process. A similar dynamic process, but for higher temperatures, was observed for buspirone (1), kaspar (2) and mesmar (3) hydrochlorides. Proton and carbon atom resonance lines have been assigned with the aid of 2D COSY and 2D HETCOR two-dimensional spectra.     

Synthesis of 8,10-dimethyl-1,10b-dihydro[1,3,5]triazino-[2,1-a]isoindole-2,4,6(3H)-trione by Direct arylation of 1,3,5-triazine-2,4(1H,3H)-dione

Direct arylation of 1,3,5-triazine-2,4(1H,3H)-dione with mesitylene afforded a novel fused heterocyclic system, 8,10-dimethyl-1,10b-dihydro[1,3,5]triazino[2,1-a]isoindole-2,4,6(3H)-trione.     

1,6-Eliminationsreaktionen an Spirocoleonon; Charakterisierung der ersten Spiro[(methylcyclopropan)-phenanthren]-1,3-dion-Derivate

Preparation of the First Spiro[(methylcyclopropan)-phenanthrene]-1,3-dione Derivatives by 1,6-Elimination Reactions of Spirocoleons Spirocoleons, e.g. coleon J ( 1 ), on treatment with 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) in aprotic solvents, undergo enolization followed by a rapid 1,6-elimination with formation of the hitherto unknown 2-methyl-spiro[cyclopropane-1,2′(1′H)-phenanthrene]-1′,3′(4′bH)-dione system, e.g. 3 . In protic solvents, base-catalyzed solvolysis of the spirocyclopropane predominates.     

[3,4]-annulated pyrroles 1. Polynuclear heterocyclic systems based on pyrrolo[3,4-d]pyrimidine-2,4-dione

The intramolecular electrophilic substitution in 6-functionalized 1,3-dimethyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-diones was used for the synthesis of pyrimido[4′,5′:3,4]-pyrrolo[1,2-a]quinoxaline-8,10(7H,9H)-dione, pyrimido[4′,5′:3,4]pyrrolo[2,1-c][1,2,4]benzo-triazine-8,10(7H,9H)-dione, and 2H-pyrimido[4′,5′:3,4]pyrrolo[1,2-a]indole-2,4,11(1H, 3H)-trione derivatives. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 12, pp. 2180–2185, December, 2006.     

Cycloaddition of singlet oxygen and 4-methyl-1,2,4-triazoline-3,5-dione (MTAD) to methoxycyclooctatetraene (MCOT)

The endoperoxides $\text{6}$ and $\text{7}$, respectively 9-methoxy- and 1-methoxy-7,8-dioxabicyclo[4.2.2]deca-2,4,7-trienes, and the urazoles $\text{8}$ and $\text{9}$, respectively 9-methoxy- and 2-methoxy-7,8-diazantricyclo[4.2.2]deca-2,4,9-trien-$\text{N}$-methyl-7,8-dicarboximide, were obtained in the cycloaddition of singlet oxygen and $\text{4}$-methyl-1,2,4-triazoline-3,5-dione (MTAD) to methoxycyclooctatetraene (MCOT).     

Synthesis of novel piperazine based building blocks: 3,7,9-triazabicyclo[3.3.1]nonane, 3,6,8-triazabicyclo[3.2.2]nonane, 3-oxa-7,9-diazabicyclo[3.3.1]nonane and 3-oxa-6,8-diazabicyclo[3.2.2]nonane

The preparation of four novel bridged piperazine building blocks is described: 3,7,9-triazabicyclo[3.3.1]nonane 1, 3-oxa-7,9-diazabicyclo[3.3.1]nonane 2, 3,6,8-triazabicyclo[3.2.2]nonane 3 and 3-oxa-6,8-diazabicyclo[3.2.2]nonane 4. The scaffold of 1 was synthesized from N,N′-dibromobenzenesulfonamide and ethyl acrylate. Compound 2 may be prepared from identical starting materials or alternatively from α,α′-diglycerol. Compounds 3 and 4 were identified as side products from possible aziridinium intermediates.