Advances in the Chemistry of 4-Azatricyclo[4.3.1.13,8]undecane (4-Azahomoadamantane) Derivatives

The review summarizes published data on the synthesis, physical and chemical properties, and biological activity of 4-azatricyclo[4.3.1.1^{3 8}]undecane derivatives and some related tricyclic compounds, tricycloundecane homologs and diadamantane derivatives.     

The conformational dependence of 15n13c spin spin coupling constants

2-Azabicyclo(2.2.2)octan-3-One 1, N-isopropylpivaloylamide 2 and 4-azatricyclo(4.3.1.1^3,8)undecan-5-one 3 have been prepared with a ¹⁵N label. The amides were reduced to the corresponding amines 2-azabicy-clo(2.2.2)octane 4, N-isopropyl-N-neopentylamine 5 and 4-azatricyclo(4.3.1.1^3,8)undecane 6. The ¹³C spectra of these compounds and their hydrochlorides were measured and the ¹⁵N¹³C spin coupling constants interpreted in terms of their conformational dependence.     

Favorskii-Umlagerung in Gegenwart von 3,4-Dimethoxyfuran: 11endo-oxa-tricyclo [4.3.1.12,5]undec-3-en-10-on und Derivate

Favorskii -rearrangement in the presence of 3,4-dimethoxyfuran: preparation of 3,4-dimethoxy 11 endo -oxo-tricyclo [4.3.1.1^2,5]undec-3-en-10-one and any derivatives On treatment with sodiumhydride of 2-chloro-cyclohexanone in the presence of 3,4-dimethoxyfuran, a possible intermediate of the Favorskii-rearrangement has been trapped as 3,4-dimethoxy-11endo-oxa-tricyclo [4.3.1.1^2,5]undec-3-en-10-one ( 3 ). This new compound contains a highly nucleophilic double bond. It can be cleaved in high yield by ozonolysis to 2exo, 4exo-bis (methoxycarbonyl)-3-oxabicyclo [3.3.1]nonan-9-one ( 4 ). Addition of chlorine to 3 occurs in stereoselective exo-cis-manner to the crystalline 3exo, 4exo-dichloro-3endo,4endo-dimethoxy 11endo-oxa-tricyclo [4.3.1.1^2,5]undecan-10-one ( 5 ). Silver ion assisted hydrolysis of 5 , followed by thermal treatment of the intermediate hydrates, leads to the red 11endo-oxa-tricyclo [4.3.1.1^2,5]undecan-3,4, 10-trione ( 6 ), and methanolysis to 3,3,4,4-tetramethoxy-11endo-oxa-tricyclo [4.3.1.1^2,5]undecan-10-one ( 8 ). By photolytic decarbonylation, 8 is converted into 3,3,4,4-tetramethoxy-10-oxa-tricyclo-[4.3.1^2,5.0]decan ( 9 ).     

Synthetic Transformations of Higher Terpenoids: X. Intramolecular Cyclization of <Emphasis Type="Italic">N</Emphasis>-Allyl- and <Emphasis Type="Italic">N</Emphasis>-Propargyl-16-dialkylammoniomethyl-12-furfuryl-13,14,15,16-tetranorlabdanoid Bromides

Quaternary ammonium salts obtained by quaternization of lambertian acid 16-dialkylaminomethyl derivatives effected by allyl halides or propargyl bromide undergo intramolecular [4+2]-cycloaddition resulting in diterpenoids of labdane type containing a heterocyclic fragment of 10-oxa-3-azatricyclo[5.2.1.0^1,5]decene or 10-oxa-3-azatricyclo[5.2.1.0^1,5]deca-6,8-diene.     

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.     

Reactivity of 5-<Emphasis Type="Italic">endo</Emphasis>-hydroxy-4-azatricyclo[5.2.1.0<Superscript>2,6</Superscript>]dec-8-en-3-ones and their isomerization initiated by acids and bases

Study of isomerization of 5-endo-hydroxy-4-azatricyclo[5.2.1.0^2,6]dec-8-en-3-ones under the action of Lewis acids (MgBr₂, AlCl₃), CF₃COOH, and NaH showed that the optimum catalyst of the process was trifluoroacetic acid. In reaction of 4-benzyl-5-endo-hydroxy-4-azatricyclo-[5.2.1.0^2,6]dec-8-en-3-one with anhydrous AlCl₃ in benzene was unexpectedly isolated N-benzyl-3-(diphenylmethyl)bicyclo[2.2.1]hept-5-ene-2-carboxamide. A convenient method was developed for the preparation of 5-exo-alkoxy-4-alkyl(aryl)-4-azatricyclo[5.2.1.0^2,6]dec- 8-en-3-ones.     

Synthesis and Some Reactions of New N-[Aryl(Benzyl,Cyclohexyl, Propyl)sulfonyl]-4-azatricyclo[5.2.1.02,6]dec-8-enes

A synthesis was accomplished of 4-azatricyclo[5.2.1.02,6]dec-8-ene by aminolysis of bicyclo[2.2.1]hept-2-ene-endo,endo-5,6-dicarboxylic acid anhydride followed by transformation of amidoacid into imide that was subsequently reduced by lithium aluminum hydride. The reaction of the key tricyclic amine with sulfonyl chlorides afforded N-[aryl(benzyl, cyclohexyl, propyl)sulfonyl]-4-azatricyclo[5.2.1.02,6]dec-8-enes.The sulfonamides were subjected to epoxidation with perphthalic acid. By reaction of sulfonamides with p-nitrophenyl azide triazolines were obtained. The structure of compounds synthesized was confirmed by IR, ^1Hand ¹³ NMR spectra.     

Synthesis of 2-Phenyl-3-oxa-5-azatricyclo[4.4.0.02 , 7]decan-4-one

Cleavage of the lactone ring in 7-phenylbicyclo[3.1.1]heptan-6,7-carbolactone by the action of ammonia and hydrazine and subsequent oxidative cyclization of the resulting hydroxy amide and hydroxy hydrazide gave a cyclic carbamate, 3-oxa-5-azatricyclo[4.4.0.0^{2 , 7}]decan-4-one.     

Synthetic transformations of higher terpenoids: XXIII. Synthesis of diterpenoid-based dihydroisoindolones

Vilsmeier-Haak reaction of phlomisoic acid methyl ester gave a mixture of 15- and 16-formyllabdanoids. In addition, methyl 2-formyldodecahydrophenanthro[1,2-b]furan-6-carboxylate was isolated, and its structure was determined by X-ray analysis. Reductive amination of 16-formyllabdanoid with benzylamine or α-amino acid methyl esters led to the formation of labdanoid furfurylamines which reacted with maleic anhydride to produce N-substituted 4-oxo-10-oxa-3-azatricyclo[5.2.1.0^1,5]dec-8-ene-6-carboxylic acids. Acylation of labdanoid furfurylamines with (E)-but-2-enoyl chloride afforded the corresponding unsaturated amides which were converted into 10-oxa-3-azatricyclo[5.2.1.0^1,5]dec-8-en-4-ones via intramolecular Diels-Alder reaction. Treatment of the oxa adducts with boron trifluoride-diethyl ether complex gave dihydroisoindol-1-one derivatives containing a diterpene fragment.     

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.     

Syntheses of Stable α-Silyloxyepoxides and α-Chloroalkyl Silyl Ethers Derivatives of 3,10-Dioxa-5-azatricyclo[5.2.1.02,6]dec-4-enes

The Diels-Alder adduct (±)-5 of furan to 1-cyanovinyl acetate was converted to (1RS,2RS,6RS,7SR,8SR,10RS)-10-{[(tert-butyl)dimethylsilyl]-oxy}-4-ethoxy (1) and -4-phenyl-3,9,11-trioxa-5-azatetracyclo[5.3.1.0^2,6.0^8,10]-undec-4-ene (2). These compounds reacted with TiCl₄ to afford stable (1RS,2RS,6RS,7SR,8SR,9SR)-9-{[(tert-butyl)dimethylsilyl]oxy}-9-chloro-4-ethoxy-3,10-dioxa-5-azatricyclo[5.2.1.0^2,6]decan-8-ol (3) and (1RS,2RS,6RS,7SR,8SR,9SR)-9-{[(tert-butyl)dimethylsilyl]oxy}-9-chloro-4-phenyl-3,10-dioxa-5-azatricyclo[5.2.1.0^2,6]decan-8-ol (4), respectively.     

Preparation of cage amine 1,3,6,8-tetraazatricyclo[4.3.1.1]undecane

Reaction between cage amine 1,3,6,8-tetraazatricyclo[4.4.1.1^3,8]dodecane (TATD) and ammonium fluoride affords 1,3,6,8-tetraazatricyclo[4.3.1.1^3,8]undecane, the missing link between 1,3,5,7-tetraazatricyclo[3.3.1.1^3,7]decane (urotropine) and TATD. The structure was established mainly from 2D NMR measurements.     

New derivatives of 2-(3,5-Dioxo-4-azatricyclo[5.2.1.0<Superscript>2,6-<Emphasis Type="Italic">endo</Emphasis></Superscript>]dec-8-en-4-yl)acetic acid. Synthesis and reactivity

New urea, carbamates, and carboxamides of the norbornene series were synthesized on the basis of 4-isocyanatomethyl-4-azatricyclo[5.2.1.0^2,6-endo ]dec-8-ene-3,5-dione, and their behavior in reactions with various electrophiles was studied. The structure of the isolated compounds was confirmed by the IR and ¹H NMR spectra.     

NMR study of 1-azatricyclo[3.3.1.13-7]decane derivatives

1-Azatricyclo[3.3.1.1^3-7]decan-4-one (4-oxo-1-azaadamantane) and 1-azatricyclo[3.3.1.1^3-7]decane-4-α(β)-ol (4-α-(β)-hydroxy-1-azaadamantane) have been studied by ¹H and ¹³C nmr methods. From this study several stereo and stereoelectronic effects have been deduced. The complete proton and carbon chemical shift assignments for the title compounds have been made, with the aid of two-dimensional nmr techniques.     

Catalytic hydrogenation of methyl 3,4-diazatricyclo-[5.2.1.0<Superscript>2,6</Superscript>]dec-4-ene-5-carboxylate

The hydrogenation at Raney nickel of the pyrazoline ring in methyl exo-3,4-diazatricyclo-[5.2.1.0^2,6]dec-4-ene-5-carboxylate takes place quantitatively with the preferential formation of the trans isomer of 5-amino-exo-3-azatricyclo[5.2.1.0^2,6]decan-4-one. The 3-methoxycarbonylmethyl-, 3-acetyl-, and 3-nitroso-substituted esters are not hydrogenated under these conditions.     

Synthesis of 5-(Benzylamino)-<Emphasis Type="Italic">exo</Emphasis>-3-azatricyclo-[5.2.1.0<Superscript>2,6</Superscript>]decan-4-one derivatives

5-(Benzylamino)-exo-3-azatricyclo[5.2.1.0^2,6]decan-4-one derivatives were synthesized in up to 94% yield by condensation of norbornane-fused 3-aminopyrrolidin-2-one with aromatic aldehydes.     

Azabrendanes. II. Chemo-, regio- and stereoselective transformation of 3-oxatricyclo[3.2.1.02,4]octane-endo-6-carbonitrile in reaction with lithium aluminum hydride

The reduction of 3-oxatricyclo[3.2.1.0^2,4]octane-endo-6-carbonitrile by lithium aluminum hydride is completed by the formation of exo-2-hydroxy-4-azatricyclo[4.2.1.0^3,7]nonane with the structure confirmed (1) by the analysis of ¹H, ¹³C, ¹⁴N, and ¹⁷O NMR spectra and the two-dimensional spectra (COSY-experiment); (2) by comparison with ¹H and ¹³C NMR spectra of the corresponding oxygen analog of heterobrendane; (3) by the calculation of the vicinal constants for the spin-spin interaction in the molecules of both analogs by the MMX program; and (4) by transformation into N-(p-bromophenylsulfonyl)-exo-2-hydroxy-4-azatricyclo[4.2.1.0^3,7]nonane prepared by an alternative synthesis, viz., epoxidation of N-(p-bromophenylsulfonyl)bicyclo-[2.2.1]hept-2-en-endo-5-methylamine. The reduction of 3-oxatricyclo [3.2.1.0^2,4]octane-exo-6-carbonitrile affords the epoxide, 3-oxatricyclo[3.2.1.0^2,4]octane-exo-6-methylamine. Different behaviors of stereoisomers are discussed; analysis of the coefficients of the atomic orbitals in the MO LCAO equation (AM1 method) has been made, and the strengths of the C(SINGLE BOND)O bonds in the epoxy ring has been analyzed. © 1997 John Wiley & Sons, Inc.     

Reactions of nitrenes with strained olefins. Nitrene additions to the bicyclo[2.2.1]hept-2-ene system

The synthesis of two examples of the 3-azatricyclo[3.2.1.0^2,4] octane ring system is described. The product azabicycles are obtained in low yields and are stable in refluxing chlorobenzene. The lead tetraacetate oxidation of 3-amino-2-methvl-4-quinazoIone leads to high yields of the deaminated compound.     

Synthetic transformations of higher terpenoids: XVII. Intramolecular cyclization of N-furfuryl amides of the labdane series

16-(Benzylaminomethyl)lambertianic acid methyl ester reacts with 2-methylprop-2-enoyl chloride to give unsaturated amide which readily undergoes intramolecular [4 + 2]-cycloaddition with formation of terpenoid derivatives of 10-oxa-3-azatricyclo[5.2.1.0^1,5]decenone. Acetylation of lambertianic acid methyl ester with acetic anhydride occurs preferentially at the 2-position of the furan ring and is accompanied by migration of the exocyclic double bond. Reductive amination of 16-acetyl-15,16-epoxylabda-8(9),13,14-triene and subsequent reaction of the resulting amine with 2-methylprop-2-enoyl chloride give intramolecular cyclization products in high yield without isolation of intermediate furfurylacryloyl derivative. Reactions of methyl 16-(benzylaminomethyl)-15,16-epoxylabda-8(9),13,14- and -8(17),13,14-trien-18-oates with maleic anhydride lead to the formation of the corresponding 10-oxa-3-azatricyclo[5.2.1.0^1,5]dec-8-ene-6-carboxylic acid derivatives as mixtures of diastereoisomers.     

Bis(trifluoromethyl)-containing 1-azatricycloheptanes

6-Substituted 7-halo-3,3-bis(trifluoromethyl)-2-azabicyclo[2.2.1]heptanes were synthesized by the addition of water, alcohols, and acetic acid to 3-halo-7,7-bis(trifluoromethyl)-1-azatricyclo[2.2.1.0^2,6]heptanes in the presence of H₂SO₄. 5,6-Disubstituted 3,3-bis(trifluoromethyl)-2-azabicyclo[2.2.1]heptanes were prepared by oxymercuration of 3,3-bis(trifluoromethyl)-2-azabicyclo[2.2.1]hept-5-ene.