Modular strategy for the synthesis of functionalized aryl-fused azabicyclo[2.2.2]octanes via radical-mediated cascade cyclization

A two-step synthesis of rare 2-azabicyclo[2.2.2]octanes is described. N-propargyl amides obtained via Cu(I)-catalyzed three-component coupling, underwent radical-mediated cascade cyclization to afford 5,6-aryl-fused 2-azabicyclo[2.2.2]octanes with arylidene functionality on the two-carbon bridge in 43–62% yields. Phenylidene and 1-naphtylidene derivatives were obtained exclusively as Z diastereomers, whereas electron rich groups in the arylidene substituent afforded product mixtures favoring the Z diastereomer by 2.3:1 M ratio.     

Aspects of the chemistry of 8-azabicyclo[3.2.1]octanes

Mesylation and elimination from dimethyl 3-hydroxy-8-azabicyclo[3.2.1]octane-2,8-dicarboxylate gave a conjugated alkenyl ester. Reduction of the mesyloxy ester by di-isobutylaluminium hydride was also accompanied by elimination giving an unsaturated aldehyde. Treatment of the mesylate of the corresponding monoprotected diol with potassium tert-butoxide gave a 2-unsubstituted alkene via a Grob fragmentation but a different alkene was obtained using 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in acetonitrile. Epoxidation of both the protected hydroxy-alkene and the free hydroxy-alkene was stereoselective in favour of epoxidation from the exo-face, and ring-opening of the hydroxy-epoxide using hydrogen bromide gave the diaxial bromohydrin. Treatment of a 2-iodomethyl-3-oxo-8-azabicyclo[3.2.1]octane with tert-butyllithium gave a cyclopropane, whereas the corresponding iodo-alcohol gave the 1-azatricyclo[5.3.0.0^4,10]decan-2-one as the major product.     

Synthesis of fluorinated 2,6-heptanediones and 2-oxa-6- azabicyclo[2.2.2]octanes from 1,4-dihydropyridines

Electrophilic fluorination of Hantzsch-type 1,4-dihydropyridines with Selectfluor^® led to the formation of new fluorinated 2,6-heptanediones - dialkyl 2,4-diacetyl-2,4-difluoro-3-phenylpentanedioates. Novel 2,6-heptanedione derivatives in reaction with hydrazine hydrate easily form 6-amino-4,7-difluoro-3-hydroxy-1,3-dimethyl-5-oxo-8-phenyl-2-oxa-6-azabicyclo[2.2.2]octanes instead of the corresponding diazepine derivatives. The obtained 2-оxa-6-azabicyclo[2,2,2]octanes are thermally stable at the temperatures below 50°С. At higher temperatures rearrangement of 2-oxa-6-azabicyclo[2,2,2]octanes offers new fluorine-containing pyrazolinone derivatives - alkyl esters of 2-fluoro-2-((4-fluoro-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-4-yl)(phenyl)methyl)-3-oxobutanoates.     

A synthesis of 6-azabicyclo[3.2.1]octanes. The role of N-substitution

The intramolecular cyclization reactions of aziridines with pi-nucleophiles can be a useful route to a number of heterocyclic and carbocyclic ring systems. We were particularly interested in the use of this cyclization reaction for the synthesis of 6-azabicyclo[3.2.1]octanes. We report here the development of a new synthesis of the aziridine necessary for the aziridine--pi-nucleophile cyclization. We also report on the cyclization of aziridines with three different substitutions on the aziridine nitrogen. We have found that N-diphenylphospinyl and N-H aziridines, while participating in the initial ring-opening reaction, do not lead to the desired bicyclic ring systems. In contrast, a nosyl group on the aziridine nitrogen leads efficiently to the bicyclic ring system and can be readily deprotected.     

A facile synthesis of a polyhydroxylated 2-azabicyclo[3.2.1]octane

Synthetic or natural aza-sugars have shown promise as a therapeutic approach to a variety of disease states by acting as transition state mimics to sugar processing enzymes. Although the synthesis of functionalized bicyclo[3.2.1]octanes has been reported, the procedures are relatively long and low yielding. Herein, we report the facile synthesis of polyhydroxylated 2-azabicyclo[3.2.1]octane that can be selectively functionalized.     

Decarbonylative radical cyclization of alpha-amino selenoesters upon electrophilic alkenes. A general method for the 6-azabicyclo[3.2.1]octane synthesis

alpha-Amino selenoester-tethered electronically poor alkenes on treatment with tributyltin hydride or TTMSS undergo intramolecular radical cyclization to provide 6-azabicyclo[3.2.1]octanes through 1-aminomethyl radical intermediates.     

Tactics for the asymmetric preparation of 2-azabicyclo[3.1.0]hexane and 2-azabicyclo[4.1.0]heptane scaffolds

In this contribution, two methods are presented for the removal of benzyl-type protecting groups attached to the nitrogen atom of 2-azabicyclo[3.1.0]hexane and 2-azabicyclo[4.1.0]heptane systems. The first, based on the Polonovski reaction, is suitable for [3.1.0] systems. The second relies on an elimination process, starting from derivatives of O-methyl phenylglycinol, and is more general in terms of the substrates tolerated. Secondary bicyclic cyclopropylamines, including enantiomerically pure molecules, can thus be accessed. These compounds are then ready for further functionalisation.     

A general and efficient synthesis of 3,6-diazabicyclo[3.2.1]octanes

A convenient and efficient synthesis of N⁶-substituted 3,6-diazabicyclo[3.2.1]octanes (6a-c) has been achieved starting from suitably substituted lactams, which were converted to nitroenamines followed by reductive cyclization to afford 3,6-diazabicyclo[3.2.1]octane-2-ones in good yields. These bicyclic lactams were then reduced to the corresponding 3,6-diazabicyclo[3.2.1]octanes and converted to the required N³,N⁶-disubstituted 3,6-diazabicyclo[3.2.1]octanes (7a-h), which were screened for α₁-adrenoceptors antagonistic activities.     

A Tandem Horner-Emmons Olefination-Conjugate Addition Approach to the Synthesis of 1,5-Disubstituted-6-azabicyclo[3.2.1]octanes Based on the AE Ring Structure of the Norditerpenoid Alkaloid Methyllycaconitine

A novel Horner-Emmons olefination conjugate addition reaction of N-acetylamides to form 1,5-disubstituted-6-azabicyclo[3.2.1]octanes with two bridgehead quarternary carbon centers is reported. This reaction is a key step in an approach to the synthesis of small ring analogues based on the AE ring structure of the Delphinium norditerpenoid, methyllycaconitine (MLA) (1). Initially, 3-(hydroxymethyl)cyclohex-2-en-1-one (10) was selected as the starting material to these structures, but its generation proved inefficient. In contrast, the synthesis of 3-[(phenylthio)methyl]cyclohex-2-en-1-one (6) and 3-(1,3-dithian-2-yl)cyclohex-2-en-1-one (11) proceeded in good yield. Subsequent hydrocyanation, ketalization, reduction, acetylation, deprotection of the acetal, and Horner-Emmons olefination-conjugate addition reaction to form 1-[(phenylthio)methyl]-5-[(ethoxycarbonyl)methyl]-6-acetamido-6-azabicyclo[3.2.1]octane (28), 1-(1,3-dithian-2-yl)-5-[(ethoxycarbonyl)methyl]-6-acetyl-6-azabicyclo[3.2.1]octane (29), respectively, are reported, as well as for readily available 3-methylcyclohex-2-en-1-one (12). Studies on the Pummerer rearrangement of 28 and subsequent desulfurization and reduction to form an hydroxymethyl-substituted azabicyclo[3.2.1.]octane (40) and then selective protection to form a protected hydroxyethyl N-ethyl (hydroxymethyl)azabicyclo[3.2.1]octane (3) are also described.     

Neighboring group participation in the additions of iodonium and bromonium ions to N-alkoxycarbonyl-2-azabicyclo[2.2.n]alk-5-enes (n = 1,2)

Additions of iodonium-X reagents to N-alkoxycarbonyl-2-azabicyclo[2.2.1]hept-5-enes and the homologous 2-azabicyclo[2.2.2]oct-5-enes have been found to mirror the outcomes of additions of bromonium-X reagents. Only rearranged products were observed for reactions of either of these halonium ion reagents with the azabicylo[2.2.1]hept-5-enes. For the azabicyclo[2.2.2]oct-5-enes, nitrogen participation in addition of IOH or BrOH was dependent on the N-alkoxycarbonyl group. With larger N-Boc, N-Cbz, or N-Troc protecting groups, unrearranged 5-anti-hydroxy-6-syn-I(or Br)-2-azabicyclo[2.2.2]octanes were formed by nucleophilic attack at C(5) on syn-halonium ions. The structure of N-methyl-8-anti-bromo-4-anti-hydroxy-2-azabicyclo[3.2.1]octane has been reassigned by X-ray analysis.     

Synthesis of N-ethoxycarbonyl-7-azabicyclo[4.2.1]nonane and N-ethoxycarbonyl-9-azabicyclo[4.2.1]nonane

The synthesis of N-ethoxycarbonyl-7-azabicyclo[4.2.1]nonane and N-ethoxycarbonyl-9-azabicyclo[4.2.1]nonane, starting from bicyclo[5.1.0]octan-2-one, is described. The key step is the cyclopropyl ring fission by pyridinium chloride.     

Cycloaddition between electron-deficient pi-systems, photochemical and radical-induced reactions: a novel, general, and stereoselective route to polyfunctionalized bridged bicyclo[2.2.2]octanes, bicyclo[3.3.0]octanes, bicyclo[4.2.0]octanes, and tricyclo[4.3.1.0(3,7)]decanes

A novel, general, and stereoselective route to functionalized bridged bicyclo[2.2.2]octanes, bicyclo[3.3.0]octanes, bicyclo[4.2.0]octanes, and tricyclo[4.3.1.0(3,7)]decanes has been described. Various functionalized and substituted bicyclo[2.2.2]octanes endowed with a beta,gamma-enone chromophore were synthesized via cycloaddition of in situ generated cyclohexa-2,4-dienones with electron-deficient 2pi partners and manipulation of the resulting adducts. Triplet sensitized irradiation of bridged bicyclooctenones led to synthesis of bicyclo[3.3.0]octanoids, whereas the direct irradiation furnished bicyclo[4.2.0]octanes in stereoselective fashion as a result of modulation of reactivity in excited states. Further, manipulation of the adducts led to appropriately appended and functionalized bicyclo[2.2.2]octanes that upon radical induced cyclization provided an efficient and stereoselective route to the tricyclo[4.3.1.0(3,7)]decane (isotwistane) framework of pupukeananes.     

Structural analysis of three methyl N-phosphorylated 5,6-dihydroxy-2-azabicyclo[2.2.1]heptane-3-carboxylates

Both exo and endo isomers of (±)-methyl N-diphenylphosphoryl-2-azabicyclo[2.2.1]hept-5-ene-3-carboxylate and (±)-methyl N-diphenylphosphoryloxy-2-azabicyclo[2.2.1]hept-5-ene-3-carboxylate were dihydroxylated with OsO₄. The unexpected formation of (±)-methyl 5,6-dihydroxy-N-diphenylphosphoryl-2-azabicyclo[2.2.1]heptane-3-endo-carboxylate from (±)-methyl N-diphenylphosphoryloxy-2-azabicyclo[2.2.1]hept-5-ene-3-endo-carboxylate is discussed based on NMR analyses and experimental observations. The two N-diphenylphosphoryl dihydroxybicycles are analyzed in terms of their crystalline structure by X-ray crystallography.     

Intramolecular hydrogen abstraction promoted by N-radicals: synthesis of chiral 7-oxa-2-azabicyclo[2.2.1]heptane and 8-oxa-6-azabicyclo[3.2.1]octane ring systems

Homochiral 7-oxa-2-azabicyclo[2.2.1]heptane and 8-oxa-6-azabicyclo[3.2.1]octane ring systems can be synthesized by reaction of specifically protected phosphoramidate derivatives of carbohydrates with (diacetoxyiodo)benzene or iodosylbenzene and iodine. The reaction mechanism goes through homolytic fragmentation of a hypothetical iodoamide intermediate. The N-radicals so generated participate in an intramolecular hydrogen abstraction reaction (IHA) to give the aforementioned bicycles.     

Synthesis of novel 2-azabicyclo[2.2.0]- and [2.1.1]hexanols

Methyl- and phenyl-substituted N-(ethoxycarbonyl)-2-azabicyclo[2.2.0]hex-5-enes 6 were reacted with NBS in wet DMSO to afford bromohydrins. Mixtures of unrearranged 6-exo-bromo-5-endo-hydroxy-2-azabicyclo[2.2.0]hexanes 7a,b and rearranged 5-anti-bromo-6-anti-hydroxy-2-azabicyclo[2.1.1]hexanes 8a,b were formed stereoselectively from the parent alkene 6a and 4-methyl alkene 6b. The 5-methyl alkene 6c affords only unrearranged bromohydrin 7c and dibromohydrin 9. By contrast, solely rearranged 3-endo-substituted-2-azabicyclo[2.1.1]hexane bromohydrins 8d-f result from additions to 3-endo-methyl alkene 6d, 3-endo-4-dimethyl alkene 6e, and 3-endo-phenyl alkene 6f. As an alternative route to bromohydrins, the parent 5,6-exo-epoxide 10a and 5-endo-methyl-5,6-exo-epoxide 10b were ring opened with bromine/triphenylphosphine to afford unrearranged 5-endo-bromo-6-exo-hydroxy-2-azabicyclo[2.2.0]hexanes 11a,b, while the 3-endo-methyl epoxide 10c afforded solely the rearranged 5-anti-bromo-6-anti-hydroxy-3-exo-methyl-2-azabicyclo[2.1.1]hexane isomer 8g. Tributyltin hydride reduction of bromohydrins 7a,b and 11a afforded novel 2-azabicyclo[2.2.0]hexan-5-ols 13a,b and -6-ol 14, and bromohydrins 8a,b, 8d-g afforded new 2-azabicyclo[2.1.1]-hexan-5-ols 15a,b and 15d-g.     

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 separation of stereoisomeric 2,4,6,8-tetrasubstituted 3,7-dithia-1,5-diazabicyclo[3.3.0]octanes

Heterocyclization of hydrazine with aldehydes R-CHO (R = Me, Et, Prⁿ, Buⁿ, n-C₅H₁₁, Ph, 4-MeOC₆H₄, 3-Py) and H₂S leads to stereoisomeric 2,4,6,8-tetrasubstituted 3,7-dithia-1,5-diazabicyclo[3.3.0]octanes, which were separated by column chromatography. The trans-transoid-trans-configuration of tetramethyl(-ethyl,-propyl)-3,7-dithia-1,5-diazabicyclo-[3.3.0]octanes was inferred from the X-ray diffraction and ¹H and ¹³C NMR spectroscopic data.     

Synthesis of 2-azabicyclo[2.1.0]pentanes by the intramolecular nucleophilic substitution of cyclopropylmagnesium carbenoids with magnesium anilide

A variety of 2-azabicyclo[2.1.0]pentanes were synthesized by the intramolecular nucleophilic substitution of cyclopropylmagnesium carbenoids with magnesium anilide. The 1-chlorocyclopropyl p-tolyl sulfoxides possessing an N-aryl-substituted aminomethyl group were prepared from dichloromethyl p-tolyl sulfoxide, α,β-unsaturated carboxylic acid esters, and anilines in four steps. The deprotonation of the amine with t-BuMgCl followed by sulfoxide/magnesium exchange of the sulfoxides with i-PrMgCl led to the generation of the cyclopropylmagnesium carbenoids possessing a magnesium anilide moiety. Subsequent intramolecular nucleophilic substitution of the cyclopropylmagnesium carbenoids occurred in a 4-exo-tet manner to give the 2-azabicyclo[2.1.0]pentanes. The optically active 2-azabicyclo[2.1.0]pentane was synthesized using a p-tolylsulfinyl group as a chiral auxiliary.     

Radical deoxygenation of 3-azatricyclo[2.2.1.0]heptan-5-ols to 2-azabicyclo[2.2.1]hept-5-enes and 1,2-dihydropyridines

Additions of alkyl or aryl Grignard reagents, or pyridin-3-yl-lithiums or lithium alkoxides, to exo-5,6-epoxy-7-(tert-butoxycarbonyl)-2-tosyl-7-azabicyclo[2.2.1]hept-2-ene lead to 7-substituted-1-tosyl-3-azatricyclo[2.2.1.0^2,6]heptan-5-ols. Radical deoxygenations of 7-alkyl-1-tosyl-3-azatricyclo[2.2.1.0^2,6]heptan-5-ols give 7-alkyl-4-tosyl-2-azabicyclo[2.2.1]hept-5-enes, whereas 7-aryl-1-tosyl-3-azatricyclo[2.2.1.0^2,6]heptan-5-ols give 2-(arylmethyl)-5-tosyl-1,2-dihydropyridines.     

Synthesis of enantiopure 2-azabicyclo[3.3.1]nonanes by a radical ring closure

The first synthesis of enantiomerically pure 2-azabicyclo[3.3.1]nonanes by an intramolecular radical reaction of the trichloroacetamido group bearing an (S)-N-1-phenylethyl substituent with the silyl enol ether moiety in compounds 7 is described. The procedure allows the two enantiomers of the 2-azabicyclo[3.3.1]nonane-3,6-dione, 3 and ent-3, to be prepared separately. β-Lactam 8 and normorphan 9 are also formed from 7 through an initial radical translocation process in the cyclization step.