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Synthesis of fused medium-ring heterocycles by the rearrangement of quaternary ammonium derivatives


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Bailey, Timothy Samuel (1994) Synthesis of fused medium-ring heterocycles by the rearrangement of quaternary ammonium derivatives. PhD thesis, University of Tasmania.

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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 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-
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

Item Type: Thesis (PhD)
Keywords: Heterocyclic compounds, Organic compounds, Ring formation (Chemistry)
Copyright Holders: The Author
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Copyright 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
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Additional Information:

Thesis (Ph.D.)--University of Tasmania, 1995. Includes bibliographic references (p. 283-292)

Date Deposited: 25 Nov 2014 00:46
Last Modified: 11 Mar 2016 05:55
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