whole_BaileyTimothySamuel1994_thesis.pdf (13.1 MB)
Synthesis of fused medium-ring heterocycles by the rearrangement of quaternary ammonium derivatives
thesisposted on 2023-05-27, 06:55 authored by Bailey, Timothy Samuel
The general aim of this study was to develop new modes of access to benzfused medium-ring heterocycles. The approach adopted was to utilise the rearrangements, with concurrent ring expansion, of heterocyclic quaternary ammonium N-ylides and N-oxides. Of particular interest were new applications of the [2,3] rearrangements of these systems. Base promoted [2,3] sigmatropic rearrangement of 1-viny1-2- ethoxycarbonylmethyl-1,2,3,4-tetrahydroisoquinolinium salts at room temperature in acetonitrile afforded functionalised 2,3,4,5-tetrahydro-1H-3-benzazonine derivatives, as mixtures of the olefinic isomers, in high yields. This is the first application of this rearrangement to the synthesis of benz-fused aza-heterocycles. A stereoselective preference for the formation of the E-benzazonines was observed. The E-benzazonines degraded to polar material on p.t.l.c. and acid-catalysed transannular interactions were proposed. The rearrangement reaction at high temperature also provided 1-vinyl-2,3,4,5-tetrahydro-1H-benzazepines, the products of [1,2] Stevens rearrangement. The mechanisms and product distributions of these rearrangements are discussed, with reference to models of the expected concerted transition states. Application of the [2,3] sigmatropic rearrangement to 1-vinyl-tetrahydroisoquinolinium salts with nitrile or phenacyl ylide stabilising groups provided the appropriate 4-substituted-2,3,4,5-tetrahydro-1H-3-benzazonine derivatives in good yields. Successful [2,3] rearrangement of the phenacyl stabilised ylide was limited to low temperatures, with Stevens rearrangement products being isolated selectively at high temperature. Rearrangement of an unstabilised methylene ylide, generated by fluorodesilylation, gave a 4-unsubstituted 3- benzazonine in low yield. Base-promoted rearrangement of N-methyl-tetrahydroisoquinolinium salts with no ylide stabilising group afforded Hofmann elimination products and demonstrated a limitation on the potential synthetic uses of the [2,3] rearrangement. Rearrangement of vinyl substituted 2-ethoxycarbonylmethyl-tetrahydroisoquinolinium salts gave, in most cases, 6- or 7-substituted-2,3,4,5-tetrahydro-1H3- benzazonine derivatives via the [2,3] rearrangement. A decrease in the Estereoselectivity of the rearrangement was observed from C1'-substituted salts and probably reflected changes in the preferred concerted transition state geometry. Limitations to the potential uses of the [2,3] rearrangement were exemplified by the rearrangements of the 2',2'-dimethyl and trans-2'-dimethoxyphenyl salts at room temperature. The former provided a mixture of the [1,2] and [2,3] rearrangement products, indicative of steric interference by the cis-2'-methyl group with the concerted transition state, while the latter gave the Stevens rearrangement product selectively, indicative of promotion of the [1,2] radical pathway by the radical stabilising group at C2'. Hydrogenation of the E -2,3,4,5-tetrahydro- 1H-3-benzazonines gave 2,3,4,5,6,7-hexahydro-derivatives, while the Z-2,3,4,5-tetrahydro-1H-3- benzazonines were unaffected. Hydrogenation of a 6-methyl-2,3,4,5-tetrahydro-1H- 3-benzazonine derivative was accompanied by a [1,3] hydrogen shift to an endocyclic olefinic 3-benzazonine. Hydrogenolysis of an N-benzyl-tetrahydro-3- benzazonine could not be obtained preferentially without concurrent hydrogenation. The reaction afforded a secondary amine derivative of the 3-benzazonine system. The [2,3] rearrangement of a 2-(tetrahydro-2'-furanon-3'-y1)-1-vinyl-tetrahydroisoquinolinium salt afforded the first example of the 2,3,4,5-tetrahydro- 1H-3-benzazonine-4-spiro-3'-tetrahydro-T-furanone ring system in low yield. An effort to extend the [2,3] rearrangement to the synthesis of unsaturated 3- benzazonines from a 1-ethynyl-tetrahydroisoquinolinium salt gave only the Stevens rearrangement product in poor yield. Thermolysis of 1-vinylic-tetrahydroisoquinolinium N-oxides unsubstituted at Cl' failed to provide [2,3] rearrangement and afforded 1-vinylic-1,3,4,5-tetrahydro- 2,3-benzoxazepines in good yield by the Meisenheimer rearrangement. Neat pyrolysis of the 1-vinyl-benzoxazepines gave an unexpected isomerisation to 1,3,3a,4,9,9a-hexahydroisoxazolo[3,4-b]naphthalene derivatives. This isomerisation may involve the formation and reaction of a nitrone intermediate. Thermolysis of 1'-substituted-l-vinylic-tetrahydroisoquinolinium N-oxides gave the first representatives of the 4,3-benzoxazonine system in mixtures with the Meisenheimer rearrangement products. The Z-olefinic 1,2,3,5-tetrahydro-4,3- benzoxazonines were formed selectively. A stereoselective concerted [2,3] rearrangement of the cis-N-oxides was indicated as thermolysis in refluxing dichloromethane gave the 4,3-benzoxazonines with unchanged trans-N-oxides. The structure of a 4,3-benzoxazonine was unequivocally established by X-ray structural analysis. The 4,3-benzoxazonines were thermally labile and in refluxing xylene gave equilibrium mixtures with, and favouring, the less-strained 1-vinylic-2,3- benzoxazepines. Meisenheimer rearrangement of a 5,6-dihydro-4H-s-triazolo[4,3-a]-1,4- benzodiazepine N-oxide afforded a 4,5-dihydro-7H-s-triazolo[4,3-a]-5,1,4- benzoxadiazocine, the first representative of this ring system, with structural similarities to the CNS active agent 'Alprazolam'. Further extension of the Meisenheimer rearrangement to tricyclic bridgehead N-oxides of the 10b-vinyl-pyrrolo[2,1-a]isoquinoline and 11b-vinyl-benzo[a]quinolizine systems gave, in low yield, the first examples of the 3,7-epoxy- 3-benzazonine and 2H-3,8-epoxy-3-benzazecine ring systems. Modification of the Meisenheimer and Stevens rearrangement to give a four atom ring expansion by the inclusion of an a-cyclopropyl substituent was also investigated. Thermolysis of a 1-cyclopropyltetrahydroisoquinoline N-oxide gave the 2,3-benzoxazepine product of the Meisenheimer rearrangement. Thermolysis of a 1-(2'-phenylcyclopropyl)tetrahydroisoquinoline N-oxide derivative gave the Meisenheimer rearrangement product and, in low yield, a 2,3,5,6-tetrahydro-5- phenyl-1H-4,3-benzoxazecine derivative. Formation of the 4,3-benzoxazecine system, the first example of this ring system, confirmed the plausibility of a modified rearrangement pathway. The 4,3-benzoxazecine structure was confirmed by X-ray crystallography. Base promoted rearrangement of the analogous 1- cyclopropyl or 1-(2'-phenylcyclopropyl)-N-ethoxycarbonylmethyl salts afforded only 3-benzazepine derivatives by the Stevens rearrangement. N-Alkylation of a 1-(2'-phenylcyclopropyl)-3,4-dihydroisoquinoline at moderate temperatures with iodometharte gave an unexpected Cloke rearrangement and a new route to the pyrrolo[2,1-a]isoquinoline system. The structure of the Nmethyl-2,3,5 ,6-tetrahydropyrrolo[2,1-a]isoquinolinium iodide product was unequivocally established by X-ray structural analysis. The global minima and low energy conformations of the 2,3,4,5-tetrahydro- 1H-3-benzazonine, 1,2,3,5-tetrahydro-4,3-benzoxazonine, and 2,3,5,6-tetrahydro- 1H-4,3-benzoxazecine systems were determined with the molecular mechanics-based program PCModel and, where possible, compared with X-ray crystallographic results. The implications of the conformers found for the properties of these compounds are discussed. It is envisaged that these studies may allow the future assessment of the potential of these compounds as CNS active agents. The present study has provided the synthesis of many novel isoquinoline derivatives necessary for the investigations described above and has established new synthetic routes to five known and six new benz-fused medium ring heterocyclic systems.
Rights statementCopyright 1994 the Author - The University is continuing to endeavour to trace the copyright owner(s) and in the meantime this item has been reproduced here in good faith. We would be pleased to hear from the copyright owner(s). Thesis (Ph.D.)--University of Tasmania, 1995. Includes bibliographic references (p. 283-292)