Synthesis of chromium carbene scaffolds for use in medicinal chemistry
- Rafael, Christopher Carlos Ferreira
- Authors: Rafael, Christopher Carlos Ferreira
- Date: 2014
- Subjects: Carbenes (Methylene compounds) , Pharmaceutical chemistry
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4456 , http://hdl.handle.net/10962/d1010863 , Carbenes (Methylene compounds) , Pharmaceutical chemistry
- Description: This study involves using methyllithium to synthesize Fischer carbene complexes as precursors for metal templated α,β-unsaturated complexes with potential as acceptors in the Baylis Hillman reaction as well as in Dötz benzannulation. Fischer carbene complexes contain low oxidation state metal centers, are electrophilic in nature and are stabilized by π-donating substituents such as alkoxy and amino groups. The increased electron withdrawing nature of the metal carbonyl moiety was expected to improve the rates of reaction compared to organic carbonyls. Four Fischer carbenes were synthesized via nucleophilic addition of MeLi to chromium and tungsten hexacarbonyl at low temperatures followed by alkylation using either a Meerwein salt (Me₃OBF₄) to give the desired Fischer metal methyl methoxy carbenes or Et₄NBr/alkylhalide to make the corresponding ethoxy and allyloxy carbenes. Characterization was by means of ¹³C NMR, ¹H NMR, and IR. In silico studies were carried out looking at the effect of substituents on the carbene bond. Synthesis of α,β-unsaturated complexes was effected via the aldol condensation route and found to be unfavorable using enolizable aldehydes, although the use of two aryl aldehydes resulted in successful preparation of two α,β-unsaturated complexes. Difficulty in the purification of these complexes hindered their full characterization. Computational studies looked at the effect of substituents on the system as well as variation of the metal from Cr to Mo and W. Synthesis of Baylis Hillman adducts using α,β-unsaturated complexes as acceptors was unsuccessful due to the ease of product oxidization. One potential product was obtained in its crude form although purification was not possible due to oxidation. Computational studies suggested that the oxygen on the ligand negatively impacts the stability of these Fischer carbene derived Baylis Hillman adducts promoting intramolecular oxidation of the metal. The α,β-unsaturated complexes and Baylis Hillman adducts were considered to be candidates to undergo Dötz benzannulation methodology. The use of the α,β-unsaturated complexes in this reaction was generally unsuccessful, both in the microwave and in conventional reflux conditions. Computational studies of these compounds were carried out to facilitate understanding of their stability and configuration.
- Full Text:
- Date Issued: 2014
- Authors: Rafael, Christopher Carlos Ferreira
- Date: 2014
- Subjects: Carbenes (Methylene compounds) , Pharmaceutical chemistry
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4456 , http://hdl.handle.net/10962/d1010863 , Carbenes (Methylene compounds) , Pharmaceutical chemistry
- Description: This study involves using methyllithium to synthesize Fischer carbene complexes as precursors for metal templated α,β-unsaturated complexes with potential as acceptors in the Baylis Hillman reaction as well as in Dötz benzannulation. Fischer carbene complexes contain low oxidation state metal centers, are electrophilic in nature and are stabilized by π-donating substituents such as alkoxy and amino groups. The increased electron withdrawing nature of the metal carbonyl moiety was expected to improve the rates of reaction compared to organic carbonyls. Four Fischer carbenes were synthesized via nucleophilic addition of MeLi to chromium and tungsten hexacarbonyl at low temperatures followed by alkylation using either a Meerwein salt (Me₃OBF₄) to give the desired Fischer metal methyl methoxy carbenes or Et₄NBr/alkylhalide to make the corresponding ethoxy and allyloxy carbenes. Characterization was by means of ¹³C NMR, ¹H NMR, and IR. In silico studies were carried out looking at the effect of substituents on the carbene bond. Synthesis of α,β-unsaturated complexes was effected via the aldol condensation route and found to be unfavorable using enolizable aldehydes, although the use of two aryl aldehydes resulted in successful preparation of two α,β-unsaturated complexes. Difficulty in the purification of these complexes hindered their full characterization. Computational studies looked at the effect of substituents on the system as well as variation of the metal from Cr to Mo and W. Synthesis of Baylis Hillman adducts using α,β-unsaturated complexes as acceptors was unsuccessful due to the ease of product oxidization. One potential product was obtained in its crude form although purification was not possible due to oxidation. Computational studies suggested that the oxygen on the ligand negatively impacts the stability of these Fischer carbene derived Baylis Hillman adducts promoting intramolecular oxidation of the metal. The α,β-unsaturated complexes and Baylis Hillman adducts were considered to be candidates to undergo Dötz benzannulation methodology. The use of the α,β-unsaturated complexes in this reaction was generally unsuccessful, both in the microwave and in conventional reflux conditions. Computational studies of these compounds were carried out to facilitate understanding of their stability and configuration.
- Full Text:
- Date Issued: 2014
An experimental and theoretical investigation of unstable Fischer chromium carbene complexes
- Authors: Makanjee, Che Azad
- Date: 2013 , 2013-03-27
- Subjects: Chromium , Organolithium compounds , Carbenes (Methylene compounds) , Organometallic chemistry , Organometallic compounds , Organochromium compounds
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4284 , http://hdl.handle.net/10962/d1002953 , Chromium , Organolithium compounds , Carbenes (Methylene compounds) , Organometallic chemistry , Organometallic compounds , Organochromium compounds
- Description: This organometallic study involves the use organostannanes and organolithiums as precursors to chromium Fischer carbene complexes. Fischer carbenes are typically electrophilic and are stabilized by a single π-donor substituent, and contain low oxidation state metals (often but not always from Group 6). They are highly reactive and can give access to a range of biologically active compounds through cyclopropanations, insertions, coupling and photochemical reactions. Synthesis and characterization of three MOM-protected α-alkoxy organostannanes was successfully carried out via a nucleophilic addition of tributylstannyllithium to suitable aldehydes, and immediate protection of the alcohol with MOM. Two N-BOC protected α-amino organostannanes were successfully synthesized and characterized via α-lithiation and tin-lithium exchange in the presence of TMEDA. Tin-lithium transmetallation of the organostannanes allowed access to the organolithiums required for the synthesis of novel Fischer carbenes. Addition of chromium hexacarbonyl to the organolithiums formed the acylpentacarbonyl chromate salt which was alkylated with Meerwein salt, resulting in the Fischer carbene and a by-product, tetrabutyltin, which proved difficult to remove. Several Fischer carbenes were synthesized and characterized, some simple and known and some novel. In silico work explored the reaction coordinate of the [2+2] cycloaddition towards the formation of β-lactams, and the photoactivation cycle that precedes this process. Computational work also showed the effect of the ligand on the stability and reactivity of the carbene. It was found that in some cases the oxygen on the ligand could negatively influence the stability of the carbene (when compared to a simple methyl carbene). A link between bond orders and back donation in Fischer carbenes was explored in an attempt to theoretically predict the stability of a range of carbenes. , Microsoft� Office Word 2007
- Full Text:
- Date Issued: 2013
- Authors: Makanjee, Che Azad
- Date: 2013 , 2013-03-27
- Subjects: Chromium , Organolithium compounds , Carbenes (Methylene compounds) , Organometallic chemistry , Organometallic compounds , Organochromium compounds
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4284 , http://hdl.handle.net/10962/d1002953 , Chromium , Organolithium compounds , Carbenes (Methylene compounds) , Organometallic chemistry , Organometallic compounds , Organochromium compounds
- Description: This organometallic study involves the use organostannanes and organolithiums as precursors to chromium Fischer carbene complexes. Fischer carbenes are typically electrophilic and are stabilized by a single π-donor substituent, and contain low oxidation state metals (often but not always from Group 6). They are highly reactive and can give access to a range of biologically active compounds through cyclopropanations, insertions, coupling and photochemical reactions. Synthesis and characterization of three MOM-protected α-alkoxy organostannanes was successfully carried out via a nucleophilic addition of tributylstannyllithium to suitable aldehydes, and immediate protection of the alcohol with MOM. Two N-BOC protected α-amino organostannanes were successfully synthesized and characterized via α-lithiation and tin-lithium exchange in the presence of TMEDA. Tin-lithium transmetallation of the organostannanes allowed access to the organolithiums required for the synthesis of novel Fischer carbenes. Addition of chromium hexacarbonyl to the organolithiums formed the acylpentacarbonyl chromate salt which was alkylated with Meerwein salt, resulting in the Fischer carbene and a by-product, tetrabutyltin, which proved difficult to remove. Several Fischer carbenes were synthesized and characterized, some simple and known and some novel. In silico work explored the reaction coordinate of the [2+2] cycloaddition towards the formation of β-lactams, and the photoactivation cycle that precedes this process. Computational work also showed the effect of the ligand on the stability and reactivity of the carbene. It was found that in some cases the oxygen on the ligand could negatively influence the stability of the carbene (when compared to a simple methyl carbene). A link between bond orders and back donation in Fischer carbenes was explored in an attempt to theoretically predict the stability of a range of carbenes. , Microsoft� Office Word 2007
- Full Text:
- Date Issued: 2013
The synthesis of α-alkoxy and α-aminostannanes as precursors to Novel Chromium Fischer Carbenes
- Authors: Meyer, Annalene
- Date: 2012
- Subjects: Alkoxides , Organometallic compounds , Carbenes (Methylene compounds) , Chromium , Molybdenum , Tungsten , Organolithium compounds
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4371 , http://hdl.handle.net/10962/d1005036 , Alkoxides , Organometallic compounds , Carbenes (Methylene compounds) , Chromium , Molybdenum , Tungsten , Organolithium compounds
- Description: The present study involves the use of main group organometallics: organostannanes and organolithiums as precursors to chromium Fischer carbene complexes. Fischer carbenes are well stabilized by the π‐donor substituents such as alkoxy and amino groups and low oxidation state metals such as Group 6 (Chromium, Molybdenum or Tungsten). Carbenes are an important intermediate in the synthesis of a range of compounds through cyclopropanations, insertions, coupling and photochemical reactions. Synthesis and successful characterisation of three α‐alkoxystannanes was achieved via nucleophilic addition of tributylstannyllithium to the respective aldehydes, followed by an immediate MOM protection of the resulting alcohol. Six α‐aminostanannes were synthesised, consisting of N‐BOC, N‐acetyl and N‐ethyl derivatives of pyrrolidine and piperidine, via α‐lithiation and subsequent tinlithium transmetallation in the presence of TMEDA. The ¹³C NMR analysis highlighted an interesting phenomenon of tin‐carbon coupling that revealed unique structural information of both types of stannanes. DFT analysis was completed on the series of stannanes; a predicted frequency analysis was obtained which complemented the experimental Infra‐red data in elucidation of the compounds. The α‐alkoxy and α‐aminostannanes provided stable precursors to the organolithiums required for the synthesis of the novel Fischer chromium carbenes. The organolithiums were obtained via tinlithium exchange at low temperatures, followed by the addition of chromium hexacarbonyl to form the acylpentacarbonyl‐chromate salt. Alkylation of this intermediate using a Meerwein salt, Me₃OBF₄, gave rise to the novel Fischer chromium carbene complexes. Fischer chromium carbenes derived from the two isomeric butyl and isobutyl stannanes and the two N‐ethyl α‐aminostannanes were successfully synthesised. The difficulty encountered in the purification of the Fischer carbene complexes hindered the full characterisation, due to the presence of a by‐product, tetrabutyltin.
- Full Text:
- Date Issued: 2012
- Authors: Meyer, Annalene
- Date: 2012
- Subjects: Alkoxides , Organometallic compounds , Carbenes (Methylene compounds) , Chromium , Molybdenum , Tungsten , Organolithium compounds
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4371 , http://hdl.handle.net/10962/d1005036 , Alkoxides , Organometallic compounds , Carbenes (Methylene compounds) , Chromium , Molybdenum , Tungsten , Organolithium compounds
- Description: The present study involves the use of main group organometallics: organostannanes and organolithiums as precursors to chromium Fischer carbene complexes. Fischer carbenes are well stabilized by the π‐donor substituents such as alkoxy and amino groups and low oxidation state metals such as Group 6 (Chromium, Molybdenum or Tungsten). Carbenes are an important intermediate in the synthesis of a range of compounds through cyclopropanations, insertions, coupling and photochemical reactions. Synthesis and successful characterisation of three α‐alkoxystannanes was achieved via nucleophilic addition of tributylstannyllithium to the respective aldehydes, followed by an immediate MOM protection of the resulting alcohol. Six α‐aminostanannes were synthesised, consisting of N‐BOC, N‐acetyl and N‐ethyl derivatives of pyrrolidine and piperidine, via α‐lithiation and subsequent tinlithium transmetallation in the presence of TMEDA. The ¹³C NMR analysis highlighted an interesting phenomenon of tin‐carbon coupling that revealed unique structural information of both types of stannanes. DFT analysis was completed on the series of stannanes; a predicted frequency analysis was obtained which complemented the experimental Infra‐red data in elucidation of the compounds. The α‐alkoxy and α‐aminostannanes provided stable precursors to the organolithiums required for the synthesis of the novel Fischer chromium carbenes. The organolithiums were obtained via tinlithium exchange at low temperatures, followed by the addition of chromium hexacarbonyl to form the acylpentacarbonyl‐chromate salt. Alkylation of this intermediate using a Meerwein salt, Me₃OBF₄, gave rise to the novel Fischer chromium carbene complexes. Fischer chromium carbenes derived from the two isomeric butyl and isobutyl stannanes and the two N‐ethyl α‐aminostannanes were successfully synthesised. The difficulty encountered in the purification of the Fischer carbene complexes hindered the full characterisation, due to the presence of a by‐product, tetrabutyltin.
- Full Text:
- Date Issued: 2012
The design and synthesis of multidentate N-heterocyclic carbenes as metathesis catalyst ligands
- Authors: Truscott, Byron John
- Date: 2011
- Subjects: Carbenes (Methylene compounds) , Heterocyclic compounds , Ligands , Ligands -- Design , Metathesis (Chemistry) , Catalysis
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4304 , http://hdl.handle.net/10962/d1004962 , Carbenes (Methylene compounds) , Heterocyclic compounds , Ligands , Ligands -- Design , Metathesis (Chemistry) , Catalysis
- Description: This study has focused on the design and preparation of bi– and tridentate N–Heterocyclic Carbene (NHC) ligands in order to investigate the effect of a multidentate approach to the formation, stability and catalytic activity of coordination complexes. Chapters 1 – 3 provide background information of relevant catalysis, carbene and coordination chemistry, followed by previous work performed within our research group. In Chapter 4 attention is given to the synthetic aspects of the research conducted, comprising two distinct approaches to the preparation of unsymmetrical saturated and unsaturated NHCs. Firstly, an investigation of the saturated NHC ligands yielded three novel, unsymmetrical pro–ligands, viz., two halopropyl imidazolinium salts and a bidentate hydroxypropyl imidazolinium salt. Secondly, eight imidazolium salts have been generated, including a hydroxypropyl analogue and novel decyl and tridentate malonyl derivatives. These compounds were prepared using microwave–assisted methodology for the alkylation of N– mesitylimidazole – an approach that drastically reduced reaction times (from 8 hours – 7 days to ca. 0.5 – 2 hours) and facilitated isolation of the imidazolium salts. Many of the compounds prepared in this study are novel and were fully characterized using HRMS and 1– and 2–D NMR analysis. Coordination studies using a selection of the prepared pro–ligands afforded an alkoxy–NHC silver derivative and four novel Ru–complexes, viz., Grubbs II–type Ru–complexes containing:– chloropropyl imidazolinylidene; propenyl imidazolylidene; and bidentate alkoxypropyl imidazolylidene ligands. Furthermore, a well–defined benzyl mesitylimidazolylidene Ru–complex has been isolated, which exhibited good stability in air. DFT–level geometry–optimization studies, using the Accelrys DMol3 package have given valuable insights into the likely geometries of the prepared and putative catalysts.
- Full Text:
- Date Issued: 2011
- Authors: Truscott, Byron John
- Date: 2011
- Subjects: Carbenes (Methylene compounds) , Heterocyclic compounds , Ligands , Ligands -- Design , Metathesis (Chemistry) , Catalysis
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4304 , http://hdl.handle.net/10962/d1004962 , Carbenes (Methylene compounds) , Heterocyclic compounds , Ligands , Ligands -- Design , Metathesis (Chemistry) , Catalysis
- Description: This study has focused on the design and preparation of bi– and tridentate N–Heterocyclic Carbene (NHC) ligands in order to investigate the effect of a multidentate approach to the formation, stability and catalytic activity of coordination complexes. Chapters 1 – 3 provide background information of relevant catalysis, carbene and coordination chemistry, followed by previous work performed within our research group. In Chapter 4 attention is given to the synthetic aspects of the research conducted, comprising two distinct approaches to the preparation of unsymmetrical saturated and unsaturated NHCs. Firstly, an investigation of the saturated NHC ligands yielded three novel, unsymmetrical pro–ligands, viz., two halopropyl imidazolinium salts and a bidentate hydroxypropyl imidazolinium salt. Secondly, eight imidazolium salts have been generated, including a hydroxypropyl analogue and novel decyl and tridentate malonyl derivatives. These compounds were prepared using microwave–assisted methodology for the alkylation of N– mesitylimidazole – an approach that drastically reduced reaction times (from 8 hours – 7 days to ca. 0.5 – 2 hours) and facilitated isolation of the imidazolium salts. Many of the compounds prepared in this study are novel and were fully characterized using HRMS and 1– and 2–D NMR analysis. Coordination studies using a selection of the prepared pro–ligands afforded an alkoxy–NHC silver derivative and four novel Ru–complexes, viz., Grubbs II–type Ru–complexes containing:– chloropropyl imidazolinylidene; propenyl imidazolylidene; and bidentate alkoxypropyl imidazolylidene ligands. Furthermore, a well–defined benzyl mesitylimidazolylidene Ru–complex has been isolated, which exhibited good stability in air. DFT–level geometry–optimization studies, using the Accelrys DMol3 package have given valuable insights into the likely geometries of the prepared and putative catalysts.
- Full Text:
- Date Issued: 2011
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