Selectfluor as a nucleofuge in the reactions of azabicyclo[n.2.1]alkane beta-halocarbamic acid esters (n = 2,3)

The ability of Selectfluor to act as a nucleofuge for hydrolysis of beta-anti-halides was investigated with N-alkoxycarbonyl derivatives of 6-anti-Y-7-anti-X-2-azabicyclo[2.2.1]heptanes and 4-anti-Y-8-anti-X-6-azabicyclo[3.2.1]octanes. The azabicycles contained X = I or Br groups in the methano bridge and Y = F, Br, Cl, or OH substituents in the larger bridge. The relative reactivities of the halides were a function of the azabicycle, the halide, and its bridge and the addition of Selectfluor or HgF(2) as a nucleofuge. All halide displacements occurred with retention of stereochemistry. Selectfluor with sodium bromide or sodium chloride, but not sodium iodide, competitively oxidized some haloalcohols to haloketones. A significant 15.6 Hz F...HO NMR coupling was observed with 4-anti-fluoro-8-anti-hydroxy-6-azabicyclo[3.2.1]octane.     

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.     

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 enantiomerically pure 1,2-diamine derivatives of 7-azabicyclo[2.2.1]heptane. New leads as glycosidase inhibitors and rigid scaffolds for the preparation of peptide analogues

Enantiomerically pure alcohols (-)- and (+)-7-tert-butoxycarbonyl-6-endo-p-toluenesulfonyl-7-azabicyclo[2.2.1]hept-2-en-5-endo-ol ((-)-11 and (+)-11) have been obtained from the Diels-Alder adduct of N-(tert-butoxycarbonyl)pyrroel and 2-bromo-1-p-toluenesulfonylacetylene, including a resolution method. These two alcohols were converted into (+)- and (-)-5-exo-amino-7-(tert-butoxycarbonyl)-2,3-exo-isopropylidenedioxy-7-azabicyclo[2.2.1]heptane ((+)-18 and (-)-18) and (+)- and (-)-5-endo-amino-7-(tert-butoxycarbonyl)-2,3-exo-isopropylidenedioxy-7-azabicyclo[2.2.1]heptane ((+)-19 and (-)-19) after adequate functionalization and desulfonylation steps. The corresponding conformationally constrained bicyclic 1,2-diamines (+)-4, (-)-4, (+/-)-5, (+/-)-6, (+)-7, and (-)-7 were obtained from the protected precursors 18 and 19 and evaluated as glycosidase inhibitors. Diamines (+)-4, (-)-4, (+)-6, and (-)-6 can be seen as new nonpeptide molecular scaffolds for the design of peptide analogues.     

Halogenation of 2-alkyl-2-azabicycloalkenes as a method for the synthesis of stable aziridinium salts of a new class

Addition of bromine and potassium dihaloiodates(i) to 2-alkyl-2-azabicyclo[2.2.1]hept-5-enes and 2-alkyl-2-azabicyclo[2.2.2]oct-5-enes affords quaternary ammonium salts containing the aziridine ring and the polyhalide anion. The possibility of using these salts for the synthesis of 6-substituted 2-alkyl-2-azabicyclo[2.2.1]heptanes has been shown.     

2-Azabicyclo[2.1.1]hexanes. 2. Substitutent effects on the bromine-mediated rearrangement of 2-azabicyclo[2.2.0]hex-5-enes

Methyl- and phenyl-substituted N-(ethoxycarbonyl)-2-azabicyclo[2.2.0]hex-5-enes 6 have been prepared by photoirradiation of appropriately substituted 1,2-dihydropyridines. Torquoselectivity is observed in the synthesis of the 3-endo-methyl- and 3-endo-phenyl-2-azabicyclo[2.2.0]hexenes 6c-e from 2-methyl- and 2-phenyl-1,2-dihydropyridines 5c-e. Products formed upon addition of bromine to 3-endo-, 4-, and 5-methyl- and 3-endo-phenyl-substituted N-(ethoxycarbonyl)-2-azabicyclo[2.2.0]hex-5-enes 6a-f were substituent dependent. For 6a,b, which lack substituents at C(3) or C(5), mixtures of unrearranged dibromides 8a,b and rearranged dibromides 9a,b were obtained. With the 3-endo-substituents in 6c-e, only rearranged dibromides 9c-e were formed; 5-methyl substitution afforded mainly unrearranged dibromide 8f and some allylic bromide 10. Both unrearranged 5-endo,6-exo-dibromo-2-azabicyclo[2.2.0]hexanes 8 and rearranged 5-anti-6-anti-dibromo-2-azabicyclo[2.1.1]hexanes 9 are formed stereoselectively. The dibromoazabicyclo[2.1.1]hexanes 9 have been reductively debrominated to afford the first reported 2-azabicyclo[2.1.1]hexanes 11 with alkyl or aryl substituents at C-3.     

Reactions of 6,6-dialkyl-5,7-dioxo-4,8-dioxaspiro[2.5]octane-1,1,2,2-tetracarbonitriles with O-centered nucleophiles

The reactions of 6,6-dialkyl-5,7-dioxo-4,8-dioxaspiro[2.5]octane-1,1,2,2-tetracarbonitriles with primary aliphatic alcohols lead to the formation of alkyl 2,2,3,3-tetracyanocyclopropanecarboxylates; the reactions of the same compounds with ketone oximes give 2-amino-4,4-bis(alkylideneaminooxy)-6-(alkylidene-aminooxycarbonyl)-3-azabicyclo[3.1.0]hex-2-ene-1,5-dicarbonitriles, while with aldehyde oximes 2-amino-2-oxo-1,5-dicyano-3-azabicyclo[3.1.0]hex-2-ene-6-carboxylic acid is formed.     

Novel catalytic kinetic resolution of racemic epoxides to allylic alcohols

[formula: see text] The kinetic resolution of racemic epoxides via catalytic enantioselective rearrangement to allylic alcohols was investigated. Using the Li-salt of (1S,3R,4R)-3-(pyrrolidinyl)methyl-2-azabicyclo [2.2.1] heptane 1 as catalyst allowed both epoxides and allylic alcohols to be obtained in an enantioenriched form.     

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.     

Synthesis of 1-azabicyclo[3.3.0]octane derivatives and their effects as piracetam-like nootropics

A useful pharmaceutical intermediate, 5-nitromethyl-1-azabicyclo[3.3.0]octane (1), was prepared in one step from 1,7-dichloro-4-heptanone (4) under mild conditions. Catalytic hydrogenation of 1 over Raney Ni in the presence of sodium hydroxide afforded 5-aminomethyl-1-azabicyclo[3.3.0]octane (2) in high yield. Piracetam analogues 20-23, which were pyrrolidine derivatives involving a 1-azabicyclo[3.3.0]octane ring, were synthesized. Pharmacological tests showed that N-[(1-azabicyclo[3.3.0]octan-5-yl)methyl]-2-oxo-1-pyrrolidineacetamid e (20) improves cerebral function.     

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.     

The rearrangement route to 3-carboxy- and 3-hydroxymethyl-2-azabicyclo[2.1.1]hexanes: 3,5-methanoprolines

Improved stereocontrolled syntheses of 5-anti-hydroxy-3-exo-methoxycarbonyl-2-azabicyclo[2.1.1]hexanes have been effected from pyridine. The key step in the electrophilic addition-rearrangement of 2-azabicyclo[2.2.0]hex-5-ene precursors incorporates either a 3-endo-phenyl group, as an acid precursor, or a 3-endo-phenyldimethylsilylmethyl group, as a potential hydroxymethyl and acid precursor.     

Diels-alder reaction of 2-chloro-2-nitrosopropane with 1,3-cyclohexadiene

3-(2-Chloropropyl)-2-oxa-3-azabicyclo[2.2.2]oct-5-ene and 2-oxa-3-azabicyclo[2.2.2]oct-5-ene hydrochloride have been prepared by cycloaddition of 2-chloro-2-nitrosopropane to 1,3-cyclohexadiene and their structure determined by nmr, using a ¹H nmr shift reagent.     

Stereocontrolled syntheses of kainoid amino acids from 7-azabicyclo[2.2.1]heptadienes using tandem radical addition-homoallylic radical rearrangement

[reaction; see text] N-Boc syn-7-(2-hydroxyethyl)-4-(alkyl or aryl)sulfonyl-2-azabicyclo[2.2.1]hept-5-enes serve as precursors in syntheses of the neuroexcitants 3-(carboxymethyl)pyrrolidine-2,4-dicarboxylic acid 43, alpha-kainic acid 12, alpha-isokainic acid 14, and alpha-dihydroallokainic acid 77. The key step in these syntheses is the intermolecular radical addition of 2-iodoethanol to a N-Boc 2-(alkyl or aryl)sulfonyl-7-azabicyclo[2.2.1]heptadiene 7 to induce nitrogen-directed homoallylic radical rearrangement. Oxidative cleavage of the resulting 2-azabicyclo[2.2.1]hept-5-enes provide straightforward access to polysubstituted pyrrolidines and, in particular, an efficient entry to the kainoid amino acids.     

Pd-Catalyzed Asymmetric 5-exo-trig Cyclization/Cyclopropanation/Carbonylation of 1,6-Enynes for the Construction of Chiral 3-Azabicyclo[3.1.0]hexanes

We herein disclose a mild and efficient access to chiral 3-azabicyclo[3.1.0]hexanes via a Pd-catalyzed asymmetric 5-exo-trig cyclization/cyclopropanation/carbonylation of 1,6-enynes. Various nucleophiles, such as alcohols, phenols, amines and water, are well compatible with the reaction system. This reaction forms three C−C bonds, two rings, two adjacent quaternary carbon stereocenters as well as one C−O/C−N bond with excellent regio- and enantioselectivities. The products could be further functionalized to generate a library of 3-azabicyclo[3.1.0]hexane frameworks.     

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.     

Reactions of 2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indole]-2,2,3,3-tetracarbonitriles with nucleophiles

2′-Oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indole]-2,2,3,3-tetracarbonitriles reacted with oxygencentered nucleophiles to form addition products at the cyano groups with conservation of the three-membered ring. Reactions of the title compounds with alcohols required the presence of base catalyst, and the products, 2-amino-4,4-dialkoxy-2′-oxo-1′,2′-dihydrospiro[3-azabicyclo[3.1.0]hex-2-ene-6,3′-indole]-1,5-dicarbonitriles, were converted into the corresponding 2-imino-2′,4-dioxospiro[3-azabicyclo[3.1.0]hexane-6,3′-indole]-1,5-dicarbonitriles and 2,2′,4-trioxospiro[3-azabicyclo[3.1.0]hexane-6,3′-indole]-1,5-dicarbonitriles by the action of acetic and sulfuric acids, respectively. The reactions with ketone oximes occurred in the absence of a catalyst, yielding 2-amino-4,4-bis(alkylideneaminooxy)-2′-oxo-1′,2′-dihydrospiro[3-azabicyclo[3.1.0]hex-2-ene-6,3′-indole]-1,5-dicarbonitriles. The reactions with thiols, aliphatic amines, and anilines were accompanied by opening of the three-membered ring. In the reactions with triphenylphosphine and thiols 2-(2-oxo-2,3-dihydro-1H-indol-3-ylidene)malononitrile was obtained, while morpholine and N,N-dimethylaniline gave rise, respectively, to 3,3-diaryl-and 3,3-dimorpholino-1H-indol-2(3H)-ones and tri- and dicyanoethylene derivatives.     

Second-chance rearrangement route to novel 5(6)-syn,anti-difunctional 2-azabicyclo[2.1.1]hexanes

[reaction: see text] The first syntheses of 5,6-difunctionalized-2-azabicyclo[2.1.1]hexanes containing syn-hydroxy and syn-fluoro substituents have been effected in a stereocontrolled manner. The key reactions are regioselective additions to the aziridinium ions formed from 6-exo-iodo(bromo)-5-endo-X-2-azabicyclo[2.2.0]hexanes (X = F, OH) upon silver or mercury salt enhancement of iodide nucleofugacity.     

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.     

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.