New applications of organocatalysis, in particular the use of the bicyclic amidine DBN (1,5-diazabicyclo[4.3.0]non-5-ene) and then iodide as nucleophilic catalysts for Friedel-Crafts reactions, have been investigated. Firstly, the use of amidines and guanidines as nucleophilic catalysts is reviewed. Amidines and guanidines are traditionally thought of as strong, non-nucleophilic bases. However, there is increasing evidence to suggest that amidines and guanidines are actually strong nucleophiles and can act as catalysts in a number of reactions. The development of the first organocatalytic Friedel-Crafts acylation reaction is then described. It was found that DBN catalyses the regioselective C2-acylation of pyrroles and C3-acylation of indoles using acyl chlorides. The protocol was shown to work for a wide range of aromatic and alkyl acyl chlorides, as well as for a number of protected pyrroles and substituted indoles. The synthetic utility of the methodology was demonstrated with the synthesis of the non-steroidal anti-inflammatory drug Tolmetin. Detailed mechanistic studies have confirmed that DBN acts as a nucleophilic catalyst in the reaction, forming an N-acyl DBN intermediate with the acyl chloride. The structure of the intermediate has been confirmed by X-ray crystallographic analysis of an N-acyl DBN species as its tetraphenylborate salt. As the N-acyl DBN tetraphenylborate salt was found to be bench stable, the use of such salts as alternatives to acyl chlorides was investigated. A number of crystalline and air stable N-acyl DBN tetraphenylborate salts were synthesised and were shown to act as acylating agents towards a wide range of nucleophiles, including primary and secondary amines, sulfonamides, and alcohols. The DBN hydrotetraphenylborate side-product could be conveniently removed from the reaction mixtures by filtration, allowing pure acylated products to be isolated without the need for column chromatography. Finally, whilst investigating the Friedel-Crafts acylation of pyrroles, it was found that lithium iodide was a highly active catalyst for the process. Preliminary mechanistic studies suggest that the iodide acts as a nucleophilic catalyst towards acyl chlorides to form an acyl iodide intermediate in the reaction
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:547629 |
| Date | January 2011 |
| Creators | Taylor, James Edward |
| Contributors | Bull, Steven ; Williams, Jonathan |
| Publisher | University of Bath |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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