The purpose of this project was to investigate whether methodology developed in
these laboratories for preparing 5/6 and 6/6 azabicyclic systems with bridged
head nitrogen can be extended to 7/6, 8/6, 9/6 and 13/6 azabicyclic systems. The
methodology entails the use of enaminones as central to the formation of the
azabicyclic systems.
The synthetic route adopted began with the Beckmann rearrangement reaction
and/or the Schmidt reaction of cyclic ketones to make lactams, which were then
thionated by Curphy or Brillon procedures. The Michael reaction of NH
thiolactams with tert-butyl acrylate was followed by Eschenmoser sulfide
contraction to afford the enaminones 132 which were utilised in the ring-closing
step. This involved hydrolysis of the tert-butyl ester and cyclisation via a mixed
anhydride. Ethyl 7-oxo-1,2,3,5,6,7-hexahydroindolizine-8-carboxylate 170b, 1-(4-
nitrobenzoyl)-3,4,6,7,8,9-hexahydroquinolizin-2-one 172a, 1-benzoyl-
3,4,7,8,9,10-hexahydropyrido[1,2-a]azepin-2(6H)-one 173d, 1-(4-nitrobenzoyl)-
3,4,6,7,8,9,10,11-octahydropyrido[1,2-a]azocin-2-one 174a, and 1-(4-
nitrobenzoyl)-3,4,7,8,9,10,11,12,13,14,17,16-dodecahydropyrido[1,2-a]azacyclotridecin-
2(6H)-one 176a were synthesised in good yields, but yields of 8-(4-
nitrobenzoyl)-2,3,5,6-tetrahydroindolizin-7(1H)-one 171a and 1-(4-nitrobenzoyl)-
3,4,7,8,9,10,11,12-octahydropyrido[1,2-a]azonin-2(6H)-one 175a were not
satisfactory. In a much shorter synthetic route that involves enaminone chemistry as well, NH
vinylogous amides were synthesised by the Eschenmoser sulfide contraction and
used in the aza-annulation reaction with acryloyl chloride. Structural isomers (to
compounds mentioned above) 8-(4-nitrobenzoyl)-2,3,6,7-tetrahydroindolizin-
5(1H)-one 178a, 1-(4-nitrobenzoyl)-2,3,7,8,9,10-hexahydropyrido[1,2-a]azepin-
4(6H)-one 180a, 1-benzoyl-2,3,7,8,9,10-hexahydropyrido[1,2-a]azepin-4(6H)-one
180b, 1-(4-nitrobenzoyl)-2,3,6,7,8,9,10,11-octahydropyrido[1,2-a]azocin-4-one 181a, 1-(4-nitrobenzoyl)-2,3,7,8,9,10,11,12-octahydropyrido[1,2-a]azonin-4(6H)-
one 182a and 1-(4-nitrobenzoyl)-2,6,7,8,9,10,11,12,13,14,15,16-
dodecahydropyrido[1,2-a]azacyclo-tridecin-4(3H)-one 183a were synthesised in
good yields. 1-(4-Nitrobenzoyl)-2,3,6,7,8,9-hexahydroquinolizin-4-one 179a was
obtained in low yield, and apparently as two conformational isomers.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:wits/oai:wiredspace.wits.ac.za:10539/5725 |
| Date | 06 October 2008 |
| Creators | Mthembu, Siyanda Thabani |
| Source Sets | South African National ETD Portal |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | application/pdf |
Page generated in 0.002 seconds