Synthesis, structure, and transformations of N-(bicyclo[2.2.1]hept-5-en-endo-2-ylmethyl)-N-[(oxiran-2-yl) methyl]-arenesulfonamides

Reaction of N-(bicyclo[2.2.1]hept-5-en-endo-2-ylmethyl)arenesulfonamides with epichlorohydrin in the presence of tetramethylammonium iodide afforded a group of framework N-[(oxiran-2-yl)methyl]sulfonamides and also a series of new dioxiranes, N-(oxiran-2-yl)methyl-N-(exo-5,6-epoxybicyclo[2.2.1]heptan-endo-2-ylmethyl)arenesulfonamides. The aminolysis of N-(oxiran-2-yl)methyl]arenesulfonamides with benzylamine and benzylpiperazine led to the chemo- and regioselective opening of the epoxy ring according to Krasusky rule. The structure of compounds was established by spectral methods and the XRD analysis.     

Synthesis,structure, and transformations of <Emphasis Type="Italic">N</Emphasis>-(alkyl-, benzyl-, arylsulfonyl)-<Emphasis Type="Italic">N</Emphasis>-(oxiran-2-ylmethyl)bicyclo[2.2.1]hept-5-en-<Emphasis Type="Italic">exo</Emphasis>-2-ylmethanamines

Reactions of N-(alkyl-, benzyl-, arylsulfonyl)bicyclo[2.2.1]hept-5-en-exo-2-ylmethanamines with 2-(chloromethyl)oxirane in the presence of tetramethylammonium iodide gave a number of cage-like N-(oxiran-2-ylmethyl)sulfonamides, as well as N-(exo-5,6-epoxybicyclo[2.2.1]heptan-exo-2-ylmethyl)-4-nitro-N-(oxiran-2-ylmethyl)benzenesulfonamide. The latter was also synthesized by oxidation of oxiran-2-ylmethyl norbornene derivative with peroxy acids. Opening of the epoxide ring in N-(oxiran-2-ylmethyl) sulfonamides in reaction with benzylamine followed the Krasuskii rule, and the aminolysis of N-(exo-5,6-epoxybicyclo[2.2.1]-heptan-exo-2-ylmethyl)-4-nitro-N-(oxiran-2-ylmethyl)benzenesulfonamide chemoselectively occurred at the side-chain epoxy group.     

Synthesis of <Emphasis Type="Italic">para</Emphasis>-substituted bicyclo[2.2.1]hept-5-en-2-ylmethyl benzoates

para-Substituted bicyclo[2.2.1]hept-5-en-2-ylmethyl benzoates were synthesized by the Diels-Alder reaction of cyclopentadiene with the corresponding para-substituted allyl benzoates, and optimal reaction conditions were found. The product structure was confirmed by independent synthesis and IR and ¹H NMR spectroscopy.     

Synthesis of quaternary 3-(1,3-dioxo-1H-isoindol-2-ylmethyl)-5,6-dihydroimidazo[2,1-b]thiazolium salts

The reaction of dihydroimidazole-2-thiol with N-(3-chloro-2-oxopropyl)phthalimide gave 2-[3-(4,5-dihydroimidazol-2-ylsulfanyl)-2-oxopropyl]-1,3-dioxo-1H-isoindole which underwent intramolecular heterocyclization to dihydroimidazothiazole system by the action of a dehydrating agent. Treatment of 3-(1,3-dioxo-1H-isoindol-2-ylmethyl)-5,6-dihydroimidazo[2,1-b]thiazole with concentrated hydrochloric acid led to the formation of dihydroimidazo[2,1-b]thiazol-3-ylmethanamine. Water-soluble quaternary 3-(1,3-dioxo-1H-isoindol-2-ylmethyl)-5,6-dihydroimidazo[2,1-b]thiazolium salts were obtained by alkylation of 3-(1,3-dioxo-1H-isoindol-2-ylmethyl)-5,6-dihydroimidazo[2,1-b]thiazole with alkyl halides.     

Spontaneous cyclization of (acridin-9-ylmethyl)thioureas to spiro [dihydroacridine-9′(10′H),5-imidazolidine]-2-thiones,a novel type of acridine spirocycles

Novel acridine spirocompounds, spiro[dihydroacridine-9′(10′H),5-imidazolidine]-2-thiones have been prepared by the spontaneous cyclization of 1-substituted 3-(acridin-9-ylmethyl)thioureas, which were obtained from 1-(acridin-9-yl)methanamine, N-(acridin-9-ylmethyl)propan-1-amine, and N-(acridin-9-ylmethyl)benzylamine and alkyl/aryl isothiocyanates, as continuation of our previous studies on new acridine spirocycles. Imidazolidine-2-thiones thus obtained were subsequently transformed with mesitylnitrile oxide to imidazolidine-2-one analogues, some of which partly reopened to the corresponding (acridin-9-ylmethyl)ureas. An unusual spirocyclization via a CH carbanion instead of the N-1 nitrogen has been found for 3-(acridin-9-ylmethyl)-1-(acridin-9-yl)thioureas possessing two acridine rings. Structural modifications in positions 1, 3, and 4 of the spiro ring together with ¹H, ¹³C, and ¹⁵N NMR spectroscopy and X-ray crystallography have been employed to rationalize a general propensity of various 9-substituted acridines to undergo easy spirocyclization.     

5,5,6-Trimethylbicyclo[2.2.1]heptan-2-one in the Synthesis of Carbocyclic Analogs of Prostaglandin Endoperoxides

1,3-Dipolar cycloaddition of nitrile oxides to 5,5,6-trimethyl-exo-2-ethynylbicyclo[2.2.1]heptan-endo-2-ol yields the corresponding 2-(isoxazol-5-yl) derivatives. Opening of the isoxazole ring in the latter gives rise to prostanoid precursors with partially built up or completed side chain. 5,5,6-Trimethyl-3-methylenebicyclo[2.2.1]heptan-2-one reacts with nitromethane in the presence of tetramethylguanidine to afford 5,5,6-trimethyl-exo-3-(2-nitroethyl)bicyclo[2.2.1]heptan-2-one which can be converted into the corresponding nitrile oxide by the action of phenyl isocyanate in benzene in the presence of triethylamine as catalyst. 1,3-Dipolar cycloaddition of the nitrile oxide to ethyl 4-pentynoate yields 3-exo-[5-(2-ethoxycarbonylethyl)isoxazol-3-ylmethyl]-5,5,6-trimethylbicyclo[2.2.1]heptan-2-one. Treatment of the latter with hydroxyl amine leads to formation of the corresponding Z-oxime whose reaction with n-hexyl bromide results in transalkylation of the ester group to afford 3-exo-[5-(2-hexyloxycarbonylethyl)isoxazol-3-ylmethyl]-5,5,6-trimethylbicyclo[2.2.1]heptan-2-one oxime.     

Synthesis of <Emphasis Type="Italic">para</Emphasis>-substituted 1,4,5,6,7,7-hexachlorobicyclo-[2.2.1]hepta-2,5-dien-2-ylmethyl benzoates

[4 + 2]-Cycloaddition of hexachlorocyclopentadiene to para-substituted prop-2-yn-1-yl benzoates gave the corresponding 1,4,5,6,7,7-hexachlorobicyclo[2.2.1]hepta-2,5-dien-2-ylmethyl benzoates. The structure of the adducts was confirmed by independent synthesis, esterification of para-substituted benzoic acids with 1,4,5,6,7,7-hexachlorobicyclo[2.2.1]hepta-2,5-dien-2-ylmethanol.     

Desymmetrization of meso 7-aza-2,3-bis(phenylsulfonyl) bicyclo[2.2.1]hept-2-ene: a re-examination. Kinetic resolution of racemic 3-arylsulfonyl-7-aza-2-bromobicyclo[2.2.1]hepta-2,5-dienes

The inexpensive large scale preparation of N-methoxycarbonyl-7-aza-2,3-bis(phenylsulfonyl)bicyclo[2.2.1]hept-2-ene and the re-examination of its stereoselective desymmetrization are reported. Moreover, the kinetic resolution of N-protected 3-arylsulfonyl-7-aza-2-bromobicyclo[2.2.1]hepta-2,5-dienes promoted by (R,R)-hydrobenzoin is described, representing a new tool to fix the absolute stereochemistry of the 7-azabicyclo[2.2.1] skeleton.     

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.     

2-Chlorobicyclo[2.2.1]hept-5-ene-2-carboxamide and 2-chlorobicyclo[2.2.1]heptane-2-carboxamide as precursors of bicyclo[2.2.1]hept-5-en-2-one and bicyclo[2.2.1]heptan-2-one: resolution,absolute configuration and hydrogen-bonding properties

The absolute configuration of bicyclo[2.2.1]heptan-2-one has not been correlated with a crystal structure of a chemical precursor. The only chemical correlation available had an ambiguity, which could have reversed the assignment. Herein, we report the resolution of 2-chlorobicyclo[2.2.1]hept-5-en-2-exo-carboxamide on a cellulose triacetate column and the crystal structures of the enantiomerically pure and racemic α-chloroamide. We found the absolute configuration (1R,2R,4R) for the (+)-enantiomer of the α-chloroamide. This compound was converted to (+)-bicyclo[2.2.1]hept-5-ene-2-one by base hydrolysis, and the 5,6-unsaturated compounds converted to the saturated congeners. This is the first unambiguous experimental determination of the absolute configuration of bicyclo[2.2.1]heptan-2-one and of bicyclo[2.2.1]hept-5-ene-2-one. The three crystal structures of 2-chlorobicyclo[2.2.1]hept-5-en-2-exo-carboxamide reported herein reveal H-bonded dimers, with two distinct orientations of the bicyclic portion relative to the carboxamide dimer. In the racemic crystal, each dimer is composed of two enantiomers, and the bicyclic portions have their bridge carbon atom (C-7) on opposite sides of the H-bonded carboxamide dimer moiety. In the enantiomerically pure crystals, the major dimer had both C-7 atoms on the same side of the carboxamide dimer moiety while the minor dimer had the C-7 atoms on opposite sides. The dimers are present in solution, and can be easily monitored.     

Synthesis of 2-(Bicyclo[2.2.1]hept-2-yloxy)ethyl Carboxylates

Esterification of aliphatic carboxylic acids with 2-(bicyclo[2.2.1]hept-2-yloxy)ethanol and 2-(5-methylbicyclo[2.2.1]hept-2-yloxy)ethanol in the presence of KU-2-8 cation exchanger (H⁺ form) afforded a series of new compounds containing both ester and ether moieties.     

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.     

Basicity of {(2-amino)- and (2-aminomethyl)bicyclo[2.2.1]hept-3-yl}anilines in nitromethane

Ionization constants of {(2-amino)-bicyclo[2.2.1]-hept-3-yl}anilines and {(2-aminomethyl)bicyclo [2.2.1]-hept-3-yl}anilines in nitromethane have been determined by potentiometric titration. Due to high values of pK _{a 1} ^BH+ and pK _{a 2} ^BH+ (close to known adamantane-containing diamines) the studied compounds are promising candidates for preparation of (co)polyimides with a complex of excellent utilitarian properties.     

Olefination of methyl (1S,2R,4R)-N-benzoyl-2-formyl-7-azabicyclo[2.2.1]heptane-1-carboxylate,a synthetic approach to new conformationally constrained prolines

Wittig olefinations of methyl (1S,2R,4R)-N-benzoyl-2-formyl-7-azabicyclo[2.2.1]heptane-1-carboxylate with several phosphoranes and the Horner–Wittig reaction, using methyl diethylphosphonoacetate, have been tested in order to evaluate their utility in the synthesis of β-substituted conformationally constrained prolines. Subsequent elaboration of the resulting alkenes has provided proline–amino acid chimeras [combinations of proline with other α-amino acids, such as l-norvaline, l-norleucine, l-α-(3-phenylpropyl)glycine or l-homoglutamic acid] with the 7-azabicyclo[2.2.1]heptane skeleton in an enantiomerically pure form.     

New N-(Arylsulfonyl)-5-aminomethylbicyclo[2.2.1]hept-2-enes. Synthesis, 1H and 13C NMR Spectra,and Chemical Reactions

A synthesis of new N-(arylsulfonyl)-5-aminomethylbicyclo[2.2.1]hept-2-enes obtained by reaction of stereoisomeric exo- and endo-5-aminomethylbicyclo[2.2.1]hept-2-enes with arylsulfonyl chlorides is described. With the use of the data of ¹H and ¹³C NMR spectra, including those of two-dimensional spectra recorded in COSY and NOESY mode, the contribution of stereochemical features of sulfonamides into the spectra structure of endo- and exo-isomers was evaluated. Applying various methods of the phase-transfer catalysis alkylation and acylation of the stereoisomeric arylsulfonamides containing a norbornene fragment was carried out. The reactions of alkylated stereoisomeric sulfonamides, N-(benzyl)-N-(3,4-dichlorophenylsulfonyl)-5-aminomethylbicyclo[2.2.1]hept-2-enes, with peroxyphthalic acid provide epoxides; the orientation of substituents in the cage norbornene fragment does not affect the direction of the process. The structure of the products obtained by sulfonamides transformations was confirmed by IR, ¹H and ¹³C NMR spectra.     

2-azatricyclo[2.2.1.01,6]heptane: Synthesis and conversion to 2-azabicyclo[2.2.1]heptanes

A facile route to 6-substituted 2-azabicyclo[2.2.1]heptanes via the novel tricyclic system, 2-azatricyclo[2.2.1.0^1,6]heptane (2), is described. The key intermediate (2) was prepared by oxidation of 4-aminomethylcyclopentene with lead tetra-acetate, and the bicyclic system was obtained by reaction of acetate with 2.MeI. Equilibration of exo- and endo-6-hydroxy-1-methyl-2-azabicyclo[2.2.1]heptane afforded an exo-endo isomeric ratio close to that of norborneol, and on this basis it is suggested that the steric requirements of the nitrogen lone pair are similar to that of CH.     

TRITHIA-DIPHOSPHABIYCLO[2.2.1]HEPTANE

Abstract

3,6-Dialkyl-2,5-Dithioxo-1,4,2λ⁵,5λ⁵-dithiadiphosphorinan-2,5-disulfides (1) react with PSCI₃, to give 3,6-Dialkyl(diaryl)-1,4-dithioxo-2,5,7-trithia-lλ⁵,4λ⁵ diphosphabicyclo[2.2.1]heptanes (2). The reaction mechanism of their formation. and the stereochemistry are discussed. By reduction of 2 with (n-C₄H₉)₃P or (C₆H₅),P 3,6-Dialkyl-2,5,7-trithia-1λ³,4λ³-diphosphabicyclo[2.2.1]heptanes (3) are formed. 2c reacts with one mole of (C₆H₅)₃P to give 3,6-Diethyl-l-thioxo-2,5,7-trithia-lλ⁵,4λ³- diphosphabicyclo(2.2.1]heptane, 4c.

3,6-Dialkyl-2,5-dithioxo-1.4,2λ⁵,5λ⁵-dithiadiphosphorinan-2,5-disulfide (I) reagieren mit PSCI₃ zu 3,6-Dialkyl(diaryl)-1,4-dithioxo-2,5,7-trithia-lλ⁵,4λ⁵-diphosphabicyclo[2.2.l]heptanen (2). Der Reaktionsmechanismus ihrer Bildung und ihre Stereochemie werden diskutiert. Die Reduktion von 2 mit (n-C₄H₉)₃,P oder (C₆H₅)₃P führt zu 3,6-Dialkyl-2,5,7-trithia-1λ³,4λ³-diphosphabicyclo[2.2.1] heptanen(3). 2c reagiert mit einer äquimolaren Menge (C₆H₅)₃,P zu 3,6-Diethyl-l-thioxo-2,5,7-trithia-lλ⁵,4λ³- diphosphabicyclo[2.2.1]heptan, 4c.     

Experimental and theoretical study on the reaction of bicyclo[2.2.1]hept-5-en-endo-2-ylmethanamine with glycidyl ethers

Reactions of bicyclo[2.2.1]hept-5-en-endo-2-ylmethanamine with phenyl, 4-methylphenyl, 3-methylphenyl, 2-methylphenyl, 4-methoxyphenyl, cyclohexyl, and cyclohexenyl 2,3-epoxypropyl ethers gave the corresponding N-mono- and N,N-bis(3-R-oxy-2-hydroxypropyl) derivatives. The structure of the newly synthesized amino alcohols and regioselectivity of oxirane ring opening were determined by IR spectroscopy, ¹H and ¹³C NMR, and mass spectrometry. The reaction mechanism was studied by quantum chemistry at the PCM/B3LYP/6-31G(d) level of theory.     

Polynuclear Iron and Rhodium Complexes of 7-Oxa[2.2.1]hericene (2,3,5,6-tetramethylidenebicyclo[2.2.1]heptan-7-one)

μ-Carbonyl(Rh? Rh)di(η⁵-indenyl)[(2R,3S)-C,2,3,C-η-(2,3,4,5-tetramethylidenebicyclo[2.2.1]heptan-7-one)]]-dirhodium(I)(Rh? Rh) (7) and cis-μ-[(2R,3S,5R,6S))-C,2,3,C-η:C,5,6,C-η-(2,3,5,6-tetramethylidenebicyclo[2.2.1]heptan-7-one)]bis[μ-carbonyldi(η⁵-indenyl)dirhodium(I)(Rh? Rh)] ( 8 ) have been prepared. Complex 7 reacts with Fe₂(CO)₉ in hexane/MeOH and gives cis-μ-[(2R,3S,5R,6S] ( 9 ), trans-μ-[(2R,3S,5S,6R)-C,2,3,C-η: C,5,6, C-η-(2,3,5,6-tetramethylidenebicyclo[2.2.1]heptan-7-one)-μ-carbonyldi(η⁵-indenyl)dirhodium(I)(Rh? Rh)-(tricarbonyliron) ( 10 ), and, μ-carbonyl(Rh? Rh)[(2R,3S)-C,2,3,C-η-(2,3-dimethyl-5,6-dimethylidenebicyclo-[2.2.1]hept-2-en-7-one)]di(η⁵-indenyl)dirhodium(I)(Rh? Rh) ( 11 ). Treatment of 7-oxa[2.2.1]hericene ( 4 ) with Fe₂(CO)₉ or (cyclooctene)₂Fe(CO)₃ gave a 1:2 mixture of cis-μ-[(2R,3S,5R,6S)-] ( 12 ) and trans-μ-[(2R,3S,5S,6R)-C,2,3,C-η:C,5,6,C-η-(2,3,5,6-tetramethylidenebicyclo[2.2.1]heptan-7-one)]bis(tricarbonyliron)( 13 ).