Application of the Baylis-Hillman methodology in the construction of novel heterocyclic derivatives
- Authors: Nyoni, Dubekile
- Date: 2008
- Subjects: Heterocyclic compounds -- Derivatives
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4402 , http://hdl.handle.net/10962/d1006704
- Description: Baylis-Hillman reactions of 2,2’-dithiodibenzaldehyde with the acyclic alkenes, methyl vinyl ketone (MVK) and methyl acrylate have afforded the thiochromene derivatives in moderate yields, and this approach has been extended to the use of the cyclic alkenes, 2-cyclohexenone and 2-cyclopentenone to afford the tricyclic analogues. In all cases, reduction of the disulphide link and intramolecular cyclisation occurred in situ, and a preliminary kinetic study of this reaction using the acyclic substrates MVK and methyl acrylate was undertaken with the aim of elucidating the mechanism involved. The results obtained showed that the consumption of both 2,2’-dithiodibenzaldehyde and MVK and/or methyl acrylate followed 1st-order kinetics during the initial stages of the reaction, but then deviated from 1st-order linearity. The reaction with methyl acrylate was much slower than with MVK, and the kinetic data indicates the mechanism to be more complex than anticipated. Conjugate addition reactions of methyl acrylate-derived 2-nitrobenzaldehyde Baylis-Hillman adducts with the amines, piperidine and benzylamine, afforded a range of conjugate addition products as diastereomeric mixtures in excellent yield (80-100%). Catalytic hydrogenation of the conjugate addition products using a Pd-C catalyst in ethanol, has afforded the corresponding, novel 3-amino-2-quinolone derivatives in lower yield (22-37%).The application of [superscript 13]C NMR prediction programmes to selected compounds synthesized in this study has revealed reasonable correlations between the experimental and predicted values.
- Full Text:
- Authors: Nyoni, Dubekile
- Date: 2008
- Subjects: Heterocyclic compounds -- Derivatives
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4402 , http://hdl.handle.net/10962/d1006704
- Description: Baylis-Hillman reactions of 2,2’-dithiodibenzaldehyde with the acyclic alkenes, methyl vinyl ketone (MVK) and methyl acrylate have afforded the thiochromene derivatives in moderate yields, and this approach has been extended to the use of the cyclic alkenes, 2-cyclohexenone and 2-cyclopentenone to afford the tricyclic analogues. In all cases, reduction of the disulphide link and intramolecular cyclisation occurred in situ, and a preliminary kinetic study of this reaction using the acyclic substrates MVK and methyl acrylate was undertaken with the aim of elucidating the mechanism involved. The results obtained showed that the consumption of both 2,2’-dithiodibenzaldehyde and MVK and/or methyl acrylate followed 1st-order kinetics during the initial stages of the reaction, but then deviated from 1st-order linearity. The reaction with methyl acrylate was much slower than with MVK, and the kinetic data indicates the mechanism to be more complex than anticipated. Conjugate addition reactions of methyl acrylate-derived 2-nitrobenzaldehyde Baylis-Hillman adducts with the amines, piperidine and benzylamine, afforded a range of conjugate addition products as diastereomeric mixtures in excellent yield (80-100%). Catalytic hydrogenation of the conjugate addition products using a Pd-C catalyst in ethanol, has afforded the corresponding, novel 3-amino-2-quinolone derivatives in lower yield (22-37%).The application of [superscript 13]C NMR prediction programmes to selected compounds synthesized in this study has revealed reasonable correlations between the experimental and predicted values.
- Full Text:
Studies towards the synthesis of novel, coumarin-based HIV-1 protease inhibitors
- Authors: Rashamuse, Thompho Jason
- Date: 2008
- Subjects: Coumarins , Protease Inhibitors , HIV infections -- Treatment , HIV (Viruses) , AIDS (Disease) -- Treatment , Heterocyclic compounds -- Derivatives
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4359 , http://hdl.handle.net/10962/d1005024 , Coumarins , Protease Inhibitors , HIV infections -- Treatment , HIV (Viruses) , AIDS (Disease) -- Treatment , Heterocyclic compounds -- Derivatives
- Description: A series of the Baylis-Hillman adducts have been obtained by reacting protected O-benzylated and unprotected substituted salicylaldehydes with methyl acrylate or tertbutyl acrylate, respectively, using DABCO as catalyst. Treatment of the Baylis-Hillman adducts with HCl in a mixture of acetic acid and acetic anhydride afforded the corresponding 3-(chloromethyl)coumarin derivatives with yields of up to 94%. Similar use of HI afforded the corresponding 3-(iodomethyl)coumarins but, depending on the reaction time, the reduced 3-methyl analogues could also be obtained. Arbuzov reactions of the 3-(halomethyl)coumarin derivatives have been undertaken to afford 4-phosphorylated and 1’-phosphorylated derivatives, regioselectivity being dependent on the halide-leaving group. The 3-(chloromethyl)coumarin derivatives have been subjected to nucleophilic (SN) attack by benzylamine to give the corresponding 3- [(benzylamino)methyl]coumarin derivatives in yields of up to 74%. Further treatment of the 3-[(benzylamino)methyl]coumarin derivatives with chloroacetyl chloride afforded the chloroacetamide derivatives, which exhibit hindered rotation about the amine C(O)-N bond. The acetamide derivatives have also been subjected to Arbuzov reaction conditions to afford the phosphorylated derivatives in yields of up to 86%. In a preliminary modelling study, hydrolysed analogues of the synthesized phosphorylated derivatives have been docked into the active site of the HIV-1 protease enzyme using the Cerius-2 Ligandfit software module to provide an insight into potential receptor-ligand hydrogen bonding interactions.
- Full Text:
- Authors: Rashamuse, Thompho Jason
- Date: 2008
- Subjects: Coumarins , Protease Inhibitors , HIV infections -- Treatment , HIV (Viruses) , AIDS (Disease) -- Treatment , Heterocyclic compounds -- Derivatives
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4359 , http://hdl.handle.net/10962/d1005024 , Coumarins , Protease Inhibitors , HIV infections -- Treatment , HIV (Viruses) , AIDS (Disease) -- Treatment , Heterocyclic compounds -- Derivatives
- Description: A series of the Baylis-Hillman adducts have been obtained by reacting protected O-benzylated and unprotected substituted salicylaldehydes with methyl acrylate or tertbutyl acrylate, respectively, using DABCO as catalyst. Treatment of the Baylis-Hillman adducts with HCl in a mixture of acetic acid and acetic anhydride afforded the corresponding 3-(chloromethyl)coumarin derivatives with yields of up to 94%. Similar use of HI afforded the corresponding 3-(iodomethyl)coumarins but, depending on the reaction time, the reduced 3-methyl analogues could also be obtained. Arbuzov reactions of the 3-(halomethyl)coumarin derivatives have been undertaken to afford 4-phosphorylated and 1’-phosphorylated derivatives, regioselectivity being dependent on the halide-leaving group. The 3-(chloromethyl)coumarin derivatives have been subjected to nucleophilic (SN) attack by benzylamine to give the corresponding 3- [(benzylamino)methyl]coumarin derivatives in yields of up to 74%. Further treatment of the 3-[(benzylamino)methyl]coumarin derivatives with chloroacetyl chloride afforded the chloroacetamide derivatives, which exhibit hindered rotation about the amine C(O)-N bond. The acetamide derivatives have also been subjected to Arbuzov reaction conditions to afford the phosphorylated derivatives in yields of up to 86%. In a preliminary modelling study, hydrolysed analogues of the synthesized phosphorylated derivatives have been docked into the active site of the HIV-1 protease enzyme using the Cerius-2 Ligandfit software module to provide an insight into potential receptor-ligand hydrogen bonding interactions.
- Full Text:
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