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Title: Synthetic studies based on nicotine
Author: Sinclair, N. M.
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 1972
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The thesis consists of an Introduction, a Discussion (divided into 6 sections) and an Experimental chapter (for sections 1 to 5 of the Discussion). The Introduction contains the justification for this work, the aim of which is to prepare new potentially valuable biologically active compounds from the readily available but highly toxic alkaloid nicotine (1). The chemistry, biological activity and metabolism of nicotine in man and animals is described. Section 1 of the Discussion reports the synthesis of alkylnicotines, prepared with the aims (a) to obtain new compounds but preserve the electronic and stereochemical parameters considered necessary for nicotine-like insecticidal activity, and (b) to prevent or reduce the rate of metabolic oxidative degradation of nicotine to the non-toxic nicotinic acid and cotinine (2). Nicotine analogues (3), (5) and (7) have been prepared by reduction of the corresponding carbonyl compounds (4), (6) and (8), which were synthesised from nicotine. The n.m.r. spectra of (3) to (8) are discussed and corroborate Craig's assignments for the n.m.r. spectrum of nicotine, a double irradiation n.m.r. spectrum of (3) supporting these assignments. The mass spectra of (3) to (8) have been recorded and interpreted with regard to the fragmentation modes for nicotine (1) and cotinine (2) as discussed by Djerassi. Compound (6) undergoes a double McLafferty rearrangement in the mass spectrometer. The 1′-oxo analogue (9) of 2′-methylnicotine has been prepared by cyclization of (10) with hydrobromic acid. Myosmine (11) and methyl magnesium iodide have given 4-methylmyosmine (12) and its mass spectrum and n.m.r. spectrum are interpreted in terms of those obtained for (11). 1-(3-Pyridyl)ethylidenemethylamine (13) has been prepared from 5-acetylpyridine and methylamine, but attempts to convert it to 2′-methylnicotine failed. Section 2 deals with oxidised nicotines. Nicotyrine (14) has been coupled with the diazonium compounds obtained from anthranilic acid and from p-nitroaniline to give (15) and (16) respectively. Although (16) appears to be active against black carpet beetle larvae neither (15) nor (16) showed useful activity in our screens. Nicotine with plenyl chloroformate gave Δ3-1-methyl-1-phenoxycarbonyl-5-(3-pyridyl)butylamine (17). The structure of pyrazole obtained from nicotine and nitric acid is discussed with reference to its mass spectrum and i.r. spectrum, the latter showing a strongly hydrogen bonded N-H stretching absorption implying structure (18b) and not (18a) as earlier supposed. Monobromo compound (19) has likewise been investigated. Nicotine and sulphur react to give dithiodinicotyrine (20) and not thiodinicotyrine as alleged earlier. A satisfactory computer simulation of the pyridine protons of (20) has been performed. Desulphurization of (20) with Raney Nickel has given nicotyrine (14). The reactions of 2- (21) and 6-aminonicotine (22) are considered in section 3. As some ureas have diuretic properties and cause reduction of intracranial and intraocular pressure compounds (25) to (29) were synthesised from (2l) and (22) with the appropriate isocyanites and isothiocyanates.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available