Carbonylations with Bridged Carbonyl Compounds as CO donors
This thesis describes research carried out to develop a norbornadienone based organic carbon monoxide releasing molecule (CORM) as a safe, solid CO source for various carbonylation reactions. Reaction of 2,5-dimethyl-3,4-diphenylcyclopentadienone dimer and bromomaleic anhydride gave cycloadduct 30 as an 8:1 inseparable mixture of the endo and exo-isomers in 96% yield. Treatment with DBU or triethylamine triggered release of CO from 30 which was then used in palladium catalysed carbonylation reactions. Ex situ generation of CO from 30 was utilised in the palladium-catalysed aminocarbonylation of p-iodoanisole (26) and n-butylamine (27) which gave N-butyl-4- methoxybenzamide (28) in 88% yield. This protocol allowed the synthesis of N-butyl-4- nitrobenzamide (45), 4-bromo-N-butylbenzamide (46), N-butylbenzamide (47) and N-butyl-1-naphthamide (48) in good to excellent yields (81 – 99%). Furthermore, tertiary amides were generated from morpholine and substituted iodobenzenes using this protocol. These were isolated in yields ranging from 72 – 99%. A room temperature double carbonylation of p-iodoanisole (26) and n-butylamine (27) with 30 as an external CO source was also carried out and the α-ketoamide product N-butyl-2-(4-methoxyphenyl)-2-oxoacetamide (54) was obtained in 64% yield. Having shown 30 to be a suitable CO donor for palladium-catalysed aminocarbonylation reactions, the protocol was adapted and applied to Suzuki-Miyaura carbonylations. Following optimisation of this reaction, the synthesis of biologically active molecules, such as the cholesterol reducing drug fenofibrate (39) was investigated. This involved the carbonylative Suzuki-Miyaura reaction of iodo-aryl ester 37 and 4-chlorophenylboronic acid (38) which was achieved in 80% yield following column chromatography. This system was also applied to the synthesis of synthetic cannabinoid compounds, which contain an indol-3-yl aryl ketone backbone. Following the successful synthesis of fenofibrate and various synthetic cannabinoids using cycloadduct 30 as a CO source, attention then turned to synthesis of analogues of the current lead compound oCOm-21, in order to provide more information about the mechanism of the CO release "trigger" of these norbornadienone-based CORMs. Following literature procedures reported by Burkart et al., maleimide 77 was converted to carboxyethoxy-maleimide 78 which was then reacted with Boc-protected ethylene diamine 79 to afford Boc-protected maleimide 80. Successive bromination and base-induced elimination gave the required mono-bromo dienophile 81 that was reacted with diene dimer 4 to give the Boc-protected cycloadduct 82 as a 2:1 mixture of the endo and exo isomers. The major endo-isomer was purified by flash chromatography and treated with 6 M HCl in 1,4-dioxane to afford oCOm-21 in 90% yield. Analogues of oCOm-21 were synthesised using a halogen exchange reaction to substitute the bromine substituent of dienophile 81 for either iodine or chlorine. The dienophiles were then reacted in the same manner with diene dimer 4 to give the Boc-protected cycloadducts 86 and 89 which could then be deprotected with 6 M HCl in 1,4-dioxane to afford oCOm- 60 and -61 respectively. The CO release profiles of oCOm-21, -60 and -61 were indirectly monitored via HPLC-MS, in order to investigate the mechanism of CO release. The rate of CO release from halo-cycloadducts increased in the order of oCOm-60 < -61 < -21 in which the elimination of HCl from oCOm-61 was proposed to occur via (E1cB)rev process, indicating the influence of the leaving group ability on the rate of elimination. The mechanism for the elimination of HX from oCOm-21 and -61 was presumed to occur via (E1cB)irr process where the deprotonation is the rate determining step.
Advisor: Larsen, David
Degree Name: Master of Science
Degree Discipline: Chemistry
Publisher: University of Otago
Keywords: New Zealand; Carbonylation; CO donor; Bridged Carbonyl Compounds; Chemistry; Organic Chemistry; Palladium-Catalysed Carbonylation; Fenofibrate; Aminocarbonylation; Suzuki-Miyaura Carbonylation; Palladium Chemistry
Research Type: Thesis