Degree Name

Doctor of Philosophy


School of Chemistry - Faculty of Science


This thesis reports on the development of new methods for the synthesis of functionalized pyrrolidines. These compounds are of important since they are the common ring structure that forms the bicyclic, heterocyclic core structure of the pyrrolizidine, indolizidine and Stemona alkaloids. In Chapter 2 we report our efforts to develop a general method for preparing 4- hydroxy-5-substituted pyrrolidin-2-ones from the borono-Mannich reactions of 4- hydroxy or 4-benzyloxy-5-hydroxypyrrolidin-2-ones with boronic acids in the presence of BF3.Et2O. The 4,5-dihydroxypyrrolidin-2-one gave in two cases 4,5-cis adducts with very high cis selectivity but in relatively low yields, while the 4- benzyloxy-5-hydroxypyrrolidin-2-one gave 4,5-trans adducts with good trans selectivity and in good to moderate yields. Unfortunately the desired dienyl 4,5-cis adduct, required for the synthesis of the Stemona alkaloids, could only be obtained in the low yield of 33%. A RCM reaction of this compound gave the desired pyrrolo[1,2-a]azepine in 72% yield. In Chapter 2 we also report the formation of a novel, Ritter reaction product, a pyrrolo[3,2-b]oxazole as an unwanted side product in the borono-Mannich reaction when acetonitrile was used as a solvent. In Chapter 3 we describe an efficient synthesis of pyrrolo[3,2-b]oxazoles from the Ritter reactions of 4-hydroxy or 4-benzyloxy-5-hydroxypyrrolidin-2-ones with nitriles in the presence of BF3.Et2O. When 4-benzyloxy-5-hydroxypyrrolidin-2-one was used as the substrate the corresponding pyrrolo[3,2-b]oxazoles were formed along with the corresponding N-benzyl amides, which were formed from the Ritter reactions of benzyl cation and the nitrile. The isolation of these amide compounds were consistent with our proposed reaction mechanism. Two of the pyrrolo[3,2- d]oxazole compounds were hydrolyzed to novel 5-acylaminopyrrolidinones. In Chapter 4 we report the metal-catalyzed cycloisomerization reactions of 3- hydroxy-2-alkynylpyrrolidine which was obtained from the borono-Mannich reaction of 2,3-dihydroxypyrrolidine and potassium phenylethynyltrifluoroborate. The cycloisomerization reaction of this pyrrolidine afforded a 2,5-disubstituted furan when Ag(I), Au(I) or Pd(II)/Cu(I) were used as a catalyst. While 3-halo-2,5- disubstituted furans were synthesized from the corresponding CuCl or CuBr vi mediated reactions. Novel 3-iodo, 3-phenyl and 3-cyano susbstituted furo[3,2- b]pyrroles were synthesized from the reactions of the 3-hydroxy-2- alkynylpyrrolidine with CuI, CuCN and PhI/Pd(dba)2, respectively. In Chapter 5 a novel method for the synthesis of 3-cyanoindoles is reported. This method showed good tolerance to electron-donating and electron withdrawing substituents on the starting ortho-alkynylaniline and allowed 3-cyanoindoles to be obtained in a single step. While the method of Wang provides 3-bromo and 3-chloro indoles in one step from ortho-alkynylanilines this method has not been extended to make 3-cyanoindoles. Future studies could involve the examination of Wang`s conditions using CuCN/O2 instead of CuBr2 or CuCl2 to prepare 3-cyanoindoles.

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