John R. Malpass

Synthesis of epibatidine homologues: Homoepibatidine and bis-homoepibatidine

Abstract Synthetic approaches are described leading to homoepibatidine and bis-homoepibatidine which are based, respectively, on the tropane (8-azabicyclo[3.2.1]octane) and homotropane (9-azabicyclo[4.2.1]nonane) ring systems. Epoxy- tropanes and -homotropanes (which are readily available from simple cyclic dienes) are convenient precursors for the azabicyclic alkenes needed for the key reductive coupling with pyridine derivatives.

Synthesis of Epibatidine Isomers: Reductive Heck Coupling of 2-Azabicyclo[2.2.1]hept-5-ene derivatives

Abstract The coupling of N-protected 2-azabicyclo[2.2.1]hept-5-enes and 2-chloro-5-iodopyridine under reductive Heck conditions gives approximately equal amounts of exo-5- and exo-6- (6′-chloro-3′-pyridyl)-2-azabicyclo[2.2.1]heptanes. The ratio varies slightly under a range of conditions but both products are isolated in every case (and in the corresponding reaction with 3-iodopyridine) contrary to a recent report that only the 5-exo- isomers are formed.

Synthesis of 5- and 6- chloropyridyl-substituted 2-azabicyclo[2.2.1]heptanes; novel epibatidine isomers

A synthetic route to the epibatidine analogue endo-5-(6-chloro-3-pyridyl)-2-azabicyclo[2.2.1]heptane and the corresponding endo-6- isomer is described, starting from a readily-available 2-azabicyclo[2.2.1]hept-5-ene derivative. Both the exo-5- and exo-6- compounds are also shown to be accessible from the same substrate using reductive Heck chemistry.

Preparation and spectroscopic studies of the 1,4-dihydro- 1,4-iminonaphthalene (7-azabenzonorbornadiene) ring system

Abstract The synthesis of a range of N-alkyl 1,4-dihydro-1,4-iminonaphthalenes (7-azabenzonorbornadienes) and reduced derivatives is described together with 1,4-dihydro-1,4- and 9,10-dihydro-9,10- iminoanthracenes. VT NMR studies lead to unambiguous assignment of invertomer preferences; changes in the invertomer ratios and nitrogen inversion barriers are investigated as the electronic and steric environment is modified by variation of substituents in the carbon skeleton and at nitrogen.

Synthetic approaches to homotropanes and homotrop-7-enes using intramolecular displacement and amidomercuration strategies

Abstract 1,4-Functionalisation of cycloocta-1,3-diene using a nitroso-cycloaddition strategy is followed by intramolecular displacement by nitrogen to yield the 9-methyl-9-azabicyclo[4.2.1]nonane (homotropane) and -non-7-ene (homotrop-7-ene) systems and N-benzyl derivatives. The approach can be adapted to allow access to 1-methylhomotropanes and -7-enes via transannular amidomercuration/de-mercuration.

A simple approach to homotropanes and homotrop-7-enes

Abstract 1,4-Functionalisatio of cycloocta-1,3-diene using a nitroso-cycloaddition strategy is followed by intramolecular cyclisation to yield 9-azabicyclo[4.2.1]nonanes (homotropanes) and -non-7-enes (homotrop-7-enes); the approach can be adapted to allow access to 1-methylhomotropanes.

Electronic control of stereoselectivity in the chlorination of 1,4-dihydro-1,4-iminonaphthalenes (7-azabenzonorbornadienes) with N-chlorosuccinimide

Abstract Chlorination of a range of secondary amines based on the 1,4-dihydro-1,4-iminonaphthalene (7-azabenzonorbornadiene) ring system is described. At low temperatures, the ratio of syn- and anti- N-chloroamines formed under conditions of kinetic control can be determined; this ratio is shown to be influenced substantially by variation in the electronic character of the aryl ring. At higher temperatures, inversion at nitrogen leads to different (thermodynamic) invertomer ratios which also vary as a function of substitution. Substituents in the aryl ring and in the bicyclic skeleton also influence the nitrogen inversion barrier.

Total Synthesis of Scopine, Pseudoscopine, and Nor- Derivatives

Abstract Scopine and pseudoscopine have been synthesised from cyclohepta-3,5-dienol; the initial 1,4-fuctionalisation of the diene is based on a nitroso- cycloaddition. The use of the N-benzyloxycarbonyl group throughout the scheme allows ultimate reductive deprotection to yield N-methyl or novel NH (nor-) derivatives without damage to the exo -epoxide of the title compounds. Preliminary investigation of nitroso- cycloaddition to 5,6-epoxycyclohepta-1,3-diene is described.

15N nuclear magnetic resonance studies of azabicycles : unusual deshielding of nitrogen in the 7-azabicyclo[2.2.1]heptyl ring system

Abstract 15N-enriched samples of derivatives of the 7-azabicyclo[2.2.1]heptyl system were synthesised and 15N NMR spectra were recorded using 15N-enriched and natural abundance samples; separate signals were observed for the two invertomers in N-methyl and N-chloro derivatives. Considerable deshielding was observed in comparison with simple amines and with 8-azabicyclo[3.2.1]octyl and 9-azabicyclo[4.2.1]nonyl analogues. Predictable changes in chemical shift resulted from substitution at nitrogen and at α-carbons; the effects of configuration at nitrogen, of unsaturation, and of substitution further from the nitrogen were also explored.

NMR studies of n-methyl derivatives of the 2-azabicyclo-[2.2.1]heptyl and -[2.2.2]octyl ring systems; kinetic protonation in determination of Invertomer preferences

Abstract The title compounds were studied by 1 H, 13 C, and 15 N NMR spectroscopy. Since inversion at nitrogen is rapid on the NMR time scale even at low temperatures, kinetic protonation was used to estimate invertomer ratios at ambient temperature. Invertomer preferences appear to be consistent with the operation of steric factors.