Synthesis and structure of 7-alkoxyalkyl-3-thia-7-zabicyclo[3.3.1]nonan-9-ones and several of their derivatives

New 7-alkoxyalkyl-3-thia-7-azabicyclo[3.3.1]nonan-9-ones were synthesized by the double Mannich cyclization of tetrahydrothiopyran-4-one with suitable alkoxyalkylamines and paraformaldehyde in acetous methanol. Wolff-Kishner decarbonylation of these bicyclic ketones gave 7-alkoxyalkyl-3-thia-7-azabicyclo[3.3.1]nonanes. The reduction of 7-alkoxyalkyl-3-thia-7-azabicyclo[3.3.1]nonan-9-ones by alkali metal hydride complexes leads to a mixture of two stereoisomeric secondary alcohols, which are epimers at C₍₉₎. Active analgesic, antiarrhythmic, and antibacterial compounds were found among these products. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 585–592, April, 2006.     

Synthesis and properties of 3-substituted 3-azabicyclo-[3.3.1]nonan-9-amines

Catalytic hydrogenation of 3-benzyl- and 3-tert-butoxycarbonyl-3-azabicyclo[3.3.1]nonan-9-one oximes over Raney nickel gave the corresponding 3-substituted 3-azabicyclo[3.3.1]nonan-9-amines which were converted into amides via reactions with acetyl and chloroacetyl chlorides and maleic and succinic anhydrides, into Schiff bases by condensation with benzaldehyde and 4-chlorobenzaldehyde, and into isothiocyanates by treatment with thiophosgene in the presence of K₂CO₃. 3-Benzyl- and 3-tert-butoxycarbonyl-3-azabicyclo-[3.3.1]nonan-9-yl isothiocyanates readily reacted with methanol, aniline, and sodium azide to produce methyl thiocarbamate, thiourea, and dihydrotetrazole-5-thione derivatives having a 3-azabicyclo[3.3.1]nonane fragment.     

Study of the Steric Structure of 7-Alkoxyalkyl-3-oxa-7-azabicyclo[3.3.1]nonan-9-ones and Their Derivatives Using 1H NMR Spectroscopy

Using the ¹H NMR spectroscopic method it has been shown that 7-alkoxyalkyl-3-oxa-7-azabicyclo[3.3.1]nonan-9-ones and 7-alkoxyalkyl-3-oxa-7-azabicyclo[3.3.1]nonanes exist in deuterochloroform solution in a double chair conformation. 7-(3-Butoxypropyl)-3-oxa-7-azabicyclo[3.3.1]nonan-9-ol is a 1:1 mixture of the two stereoisomeric alcohols. One of them exists in a double chair conformation having an equatorial hydroxyl group with relation to the piperidine ring and the other in a chair-boat conformation having an axial hydroxyl group which involves an intramolecular hydrogen bond with the unshared electron pair of the nitrogen atom.     

Synthesis and study on 2,4,6,8-tetraaryl- 3,7-diazabicyclo[3.3.1]nonanes and their derivatives

1-Carbethoxy-2,4,6,8-tetraaryl-3,7-diazabicyclo[3.3.1] nonan-9-ones (1, 2) were synthesized and their 1H and 13C NMR data are reported. Chemical shifts and spectral assignments for 2,4,6,8-tetrakis(4-chlorophenyl)-3,7-diazabicyclo[3.3.1]nonan-9-one (3), 2,4,6,8-tetraphenyl-3-thia-7-azabicyclo[3.3.1]nonan-9-one (4) and 2,4,6,8-tetraaryl-3,7-diazabicyclo[3.3.1]nonanes (5-7) are also included.     

Reactions of 3-substituted 3-azabicyclo[3.3.1]nonan-9-ones with nitrogen-containing nucleophiles

Condensation of 3-substituted 3-azabicyclo[3.3.1]nonan-9-ones with hydroxylamine and hydrazine hydrate gave the corresponding oximes, hydrazones, and azines. Reductive amination of the title compounds in the presence of sodium triacetoxyhydridoborate led to the formation of 3-substituted 3-azabicyclo[3.3.1]nonan-9-amines which were converted into the corresponding dihydrochlorides by treatment with dry hydrogen chloride. Treatment of 3-tert-butoxycarbonyl derivatives with HCl under analogous conditions was accompanied by elimination of the tert-butoxycarbonyl group to produce 3-azabicyclo[3.3.1]nonan-9-amine dihydrochlorides.     

Synthesis and Properties of 3-Thia-9-azabicyclo[3.3.1]nonan-7-one

N-Benzyl-3-thia-9-aza-bicyclo[3.3.1]nonan-7-one has been prepared from methyl 4-bromocrotonate by reaction sequence involving sodium sulfide, benzylamine, and Dieckmann condensation. Some spectral and chemical properties of this system are also reported.     

Spectroscopic study of 3-methyl-2,4-diphenyl-3-azabicyclo[3.3.1]nonan-9-α(β)-ols

3-Methyl-2,4-diphenyl-3-azabicyclo[3.3.1]nonan-9-α(β)-ols have been synthesized and studied by ir, ¹H and ¹³C nmr spectroscopy. In deuteriochloroform and perdeuteriobenzene solutions, these compounds adopt a flattened chair-chair conformation in which the cyclohexane ring is more flattened. From the ¹H and ¹³C nmr data, several stereoelectronic effects have been deduced. The complete and unambiguous assignment of all protons of the 3-azabicyclo[3.3.1]nonane system, not described up to date, has been carried out.     

Synthèse de spirohydantoines dérivées du diphényl-2,4-aza-3-bicyclo-[3.3.1]nonane et du diphényl-7,9-aza-8-bicyclo[4.3.1]decane par réaction de Bucherer dans la N,N-diméthylformamide: Influence de la température et cours stéréochimique. Communication préliminaire

Synthesis of Spyrohydantoines Derivatives of 2,4-Diphenyl-3-azabicyclo[3.3.1]nonane and 7,9-Diphenyl-8-azabicyclo[4.3.1]decane via Bucherer Reaction in N,N-Dimethylformamide: Influence of the Temperature and Stereochemical Path The unreactives ketones related to 2,4-diphenyl-3-azabicyclo [3.3.1]nonan-9-one to the Bucherer reaction in usuals conditions show excellent reactivity in DMF. as unique solvant. The stereochemical paths of these reactions and the synthetic utility of the temperature modification are described.     

New homoleptic metal complexes of Schiff bases derived from 2,4-di-p-tolyl-3-azabicyclo[3.3.1]nonan-9-one

New bidentate Schiff-base ligands 2-(2,4-di-p-tolyl-3-azabicyclo[3.3.1]nonan-9-ylidene)hydrazinecarbothioamide HL¹ and 2-(2,4-di-p-tolyl-3-azabicyclo[3.3.1]nonan-9-ylidene)hydrazinecarboxamide HL² were synthesized from the condensation of 2,4-di-p-tolyl-3-azabicyclo[3.3.1]nonan-9-one with thiosemicarbazide and semicarbazide, respectively. Homoleptic complexes of these ligands, of general formula K[Cr(L ⁿ )₂Cl₂], K₂[Mn(L ⁿ )₂Cl₂], K₂[Fe(L¹)₂Cl₂] and [M(L ⁿ )₂] (where M = Co(II), Ni(II) Cu(II), Zn(II), Cd(II), and Hg(II) ions; n = 1 or 2) are reported. The mode of bonding and overall geometry of the complexes were determined through IR, UV-Vis, NMR and mass spectral studies, magnetic moment measurements, elemental analysis, metal content, and conductance. These studies revealed octahedral geometry for Cr(III), Mn(II), and Fe(II) complexes, square planar for Cu(II), Co(II), and Ni(II) complexes and tetrahedral for Zn(II), Cd(II), and Hg(II) complexes.     

<Superscript>1</Superscript>H NMR spectroscopy in the study of the three-dimensional structure of 7-alkoxyalkyl-3-thia-7-azabicyclo-[3.3.1]nonan-9-ones and some of their derivatives

¹H NMR spectroscopy was used to establish that 7-alkoxyalkyl-3-thia-7-azabicyclo[3.3.1]nonan-9-ones and their decarbonylated derivatives in deuterochloroform solution exist in the double chair conformation. The predominantly formed secondary alcohols isomers have preferred double chair conformation with the hydroxyl group equatorial relative to the plane of the piperidine ring. On the other hand, the epimeric alcohols have predominant boat-chair conformation; the piperidine ring takes the boat form due to intramolecular hydrogen bonding between the unshared electron pair of the nitrogen atom and hydroxyl group proton. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1716–1725, November, 2008.     

Chemistry of 3-Azabicyclo[3.3.1]nonane: II. Reduction of 6-Acetoxy-3-benzyl-1- ethoxycarbonyl-3-azabicyclo[3.3.1]nonan-9-one with Sodium Borohydride

Reduction of 6-acetoxy-3-benzyl-l-ethoxycarbonyl-3-azabicyclo[3.3.1]nonan-9-one with sodium borohydride was investigated in various conditions. The stereochemistry of reduction products was deduced from ¹H and ¹³C NMR and mass spectra.     

Synthesis, structural and crystallographic study of some carbamates derived from 9-methyl-9-azabicyclo[3.3.1]nonan-3α-ol

A series of benzimidazole, thiazole and benzothiazole carbamates derived from 9-methyl-9-azabicyclo[3.3.1]nonan-3α-ol was synthesized and studied by ¹H, ¹³C, 2D NMR and IR spectroscopy. To assist in the interpretation of the spectroscopic data, the crystal structure of 3 (9-methyl-9-azabicyclo[3.3.1]nonan-3α-yl 2-amino-1H-benzimidazole-1-carboxilate) was determined by X-ray diffraction. It has been found that 1-carbamates and 2-carbamates can be obtained in the case of the benzimidazole derivatives. The benzimidazole-1-carbamates are obtained in higher yields (41, 38%) than the benzimidazole-2-carbamates (3, 9%). The compounds studied displayed in CDCl₃ solution a preferred chair–boat conformation with the substituted ring in a distorted boat form and the N–CH₃ substituent in an axial position with respect to the chair piperidine ring. This conformation is similar to that determined by X-Ray diffraction for compound 3.     

Conformational and configurational studies on 3-azabicyclo[3.3.1]nonane (3-abn) derivatives and related systems employing carbon-13 NMR spectroscopy

The ¹³C nmr spectra of 4 cis-2,4-diphenyl-3-azabicyclo[3.3.1]nonanes, 11 cis-2,4-diaryl-3-azabicyclo[3.3.1]-nonan-9-ones, 26 cis-2,4-diaryl-3-azabicyclo[3.3.1]-nonan-9-ols or acetates thereof, 5 cis-2,4-diaryl-3-azabi-cyclo[4.3.1]decan-10-ones or -10-ols and 5 cis-2,4-diphenyl-3-aza-7-thiabicyclo[3.3.1]nonan-9-ones, -9-ols or 9-yl acetates have been recorded. Except for the 7-thia compounds, which appear to exist mainly in the configuration and conformation with the nitrogen-containing ring in the boat form, these compounds seem to exist overwhelmingly in chair-chair conformations. The configuration of the 9-ols and their acetates (syn or anti to the nitrogen-containing ring) has been deduced from the spectra. In a number of cases, the structures assigned differ from those earlier postulated. Broadening of one set of aryl signals (probably those due to the ortho carbons) in the case of N-methyl (but not N-H) compounds without ortho substituents is ascribed to restricted phenyl rotation.     

Functionalized 2-azabicyclo[3.3.1] nonanes. vii.: A new synthesis of 4-azatricyclo[5.2.2.04,8]undecan-11-one

An improved method for the synthesis of 4-azatricyclo [5.2.2.0⁴,⁸] undecan-11-one (1) is reported. The synthesis involves hydrogenolysis of 8-hydroxyethyl-2-azabicyclo [3.3.1] nonan-7-one 3 followed by intramolecular alkylation of the resulting secondary amine 7. The required azabicyclic alcohol 3 was obtained by oxidative cyclization with mercuric acetate of the α-alkylated methyl 4-piperidineacetoacetate 5.     

Reactions of N-substituted 3-azabicyclo[3.3.1]nonan-9-ones with N,N-, N,S-, and N,O-binucleophiles

Condensation of N-substituted 3-azabicyclo[3.3.1]nonan-9-ones with difunctional N,N-, N,S-, and N,O-centered nucleophiles (o-phenylenediamine, 1,2-diphenylethane-1,2-diamine, 2-aminobenzenethiol, cysteine, 2-aminophenol, serine) gave the corresponding spiro heterocyclic compounds fused at the C⁹ atom. Treatment of N-tert-butoxycarbonyl-substituted spiro compounds with anhydrous hydrogen chloride resulted in elimination of the tert-butoxycarbonyl group with formation of spiro[3-azabicyclo[3.3.1]nonane-9,2′-azole] hydrochlorides.     

3- Substituted 3- Azabicyclo[3.3.1]nonan- 9- ols and Their Transformations Involving the Hydroxy Group

The reduction of 3-benzyl- and 3-tert-butoxycarbonyl-3-azabicyclo[3.3.1]nonan-9-ones with sodium tetrahydridoborate gave the corresponding alcohols as mixtures of á- and ä-epimers at a ratio of 2: 3. The resulting alcohols reacted with acetyl chloride and methanesulfonyl chloride at the hydroxy group to form O-acetyl and O-methylsulfonyl derivatives. Reactions of the latter with potassium iodide and sodium azide afforded 3-substituted 9-iodo(azido)-3-azabicyclo[3.3.1]nonanes. 9-Iodo derivatives were treated with triphenylphosphine to obtain triphenylphosphonium salts which were converted into the corresponding phosphonium ylides by the action of sodium methoxide in methanol, and the ylides readily reacted with benzaldehyde according to Wittig.     

Molecular structure of 3,7-dimethyl-9-thia-3,7-diazabicyclo[3.3.1]nonane-9,9-dioxide

By a single crystal X-ray diffraction study the molecular structure of 3,7-dimethyl-9-thia-3,7-diazabicyclo[3.3.1]nonane-9,9-dioxide having a chair-chair conformation with a diequatorial arrangement of methyl groups at nitrogen atoms is determined. Compound 1 C₈H₁₆N₂O₂S crystallizes in the space group Pnma with the following cell parameters: a = 11.0262(3) Å, b = 14.4490(3) Å, c = 6.1780(3) Å.     

Synthetic and structural study of 4-phosphacyclohexanones and 3-aza-7-phosphabicyclo[3.3.1]nonan-9-ones

The synthesis of bicyclic phosphorus–nitrogen (PN) compounds containing the rigid bicyclo[3.3.1]nonan-9-one framework was attempted using the Mannich condensation reaction of four different phosphorinanone classes with amines and aldehydes. Three different isomers of 4-tert-butyl-2,6-di(methoxycarbonyl)-3,5-bis(p-dimethylaminophenyl)-4-phosphacyclohexanone were obtained from the Michael addition reaction of tert-butylphosphine with 2,4-di(methoxycarbonyl)-1,5-bis(p-dimethylaminophenyl)penta-1,4-dien-3-one. The reaction of the all-equatorial isomer with methylamine and formaldehyde produced the bicyclic PN compound 7-tert-butyl-1,5-di(methoxycarbonyl)-6,8-bis(p-dimethylaminophenyl)-3-methyl-3-aza-7-phosphabicyclo[3.3.1]nonan-9-one. The identical Mannich reaction of the enol tautomer also yielded the same product, as well as the PN compound 4-tert-butyl-6-methoxycarbonyl-5-(p-dimethylaminophenyl)-2-methyl-2-aza-4-phosphacyclohexanone and the E/Z isomers of 3-(p-dimethylaminophenyl)methyl-2-propenoate. The newly synthesised 3-aza-7-phosphabicyclo[3.3.1]nonan-9-one PN compound adopts a chair–chair conformation both in solution and the solid state.     

Assymetric syntheses of the ladybug alkaloid adaline and 1-methyl-9-azabicyclo [3.3.1]nonan-3-one

The double Michael addition of benzylamine to 3-alkyl-2,7-cyclooctadienones, followed by hydrogenolysis, affords bridgehead substituted 9-azabicyclo[3.3.1]nonan-3-ones. Use of (+)-α-methylbenzylamine in the addition leads to mixtures of diastereomeric adducts in unequal amounts. Although the degree of asymmetric induction is low (10–20% ee), the diastereonomers can be easily separated, affording pure enantiomeric forms of the ladybug alkaloid adaline 1 and the Euphorbia alkaloid 3.     

Structural study of 3-methyl-2,4-diphenyl-3-azabicyclo[3.3.1]nonan-9β-ol

The infrared spectra in several media and the crystal structure of 3-methyl-2,4-diphenyl-3-azabicyclo[3.3.1]-nonan-9β-ol ( I ) (Scheme I) have been determined, in order to complete the structural study described for the title compound from the ¹H and ¹³C nmr data [1]. The bicyclic system adopts a flattened chair-chair conformation in which the cyclohexane ring is more flattened. The methyl and phenyl groups are in equatorial positions and the OH group in an axial position with respect to the piperidine ring.