The synthesis of novel nitrogen containing heterocycles

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

Intermolecular addition reactions of N-acyliminium ions (Part II)

This review highlights the advances in the literature up to July 2008 on the intermolecular reactions of acyclic and cyclic N-acyliminium ions. This is an update of an earlier review in 2000 oil this topic and does not include intramolecular addition reactions to N-acyliminium ions which was recently reviewed. This review is presented in two parts, with the first part having dealt with acyclic and pyrrolidinone-based N-acyliminium ions. Part II continues with other five-membered heterocyclic derivatives and higher systems

Synthesis of 3-halo-2,5-disubstituted furans via CuX mediated cyclization-halogenation reactions

The Cu(I) halide (X = I, Br, Cl) mediated reactions of Cbz-protected cis-2-phenylethenyl-3-hydroxypyrrolidine gave novel 3-halo-2,5-trisubstituted furans in good yields, via a cyclization-halogenation, ring-opening reaction sequence. In contrast, the reactions with CuCN gave mainly the corresponding 3-cyanofuro[3,2-b]pyrrole formed from a cyclization-cyanation reaction

Sequential 1,4- and 1,2-addition reactions to α,β-unsaturated N-acyliminium ions: a new strategy for the synthesis of spiro and bridged heterocycles

Novel bicyclic and tetracyclic spirocycles and tricyclic bridged heterocyclic systems can be readily prepared from sequential 1,4- and 1,2-addition reactions of latent bis-nucleophiles to α,β-unsaturated N-acyliminium ions

Intermolecular addition reactions of N-acyliminium ions (Part I)

This review highlights the advances in the literature up to July 2008 on the intermolecular reactions of acyclic and cyclic N-acyliminium ions. This is an update of an earlier review in 2000 on this topic and does not include intramolecular addition reactions to N-acyliminium ions which was recently reviewed. This review is presented in two parts, with the first part dealing with acyclic and pyrrolidinone-based N-acyliminium ions. Part II continues with other five-membered heterocyclic derivatives and higher systems

Copper-mediated cyclization-halogenation and cyclization-cyanation reactions of β-hydroxyalkynes and o-alkynylphenols and anilines

The CuX (X = I, Br, Cl, CN)-mediated cyclization-halogenation and cyclization-cyanation reactions of β-hydroxyalkynes and o-alkynylphenol and -aniline derivatives give rise to 3-halo- and 3-cyanofuro[3,2-b]pyrroles, 3-iodo-, 3-bromo-, and 3-cyanobenzofurans, and 3-cyanoindoles, respectively. © 2010 American Chemical Society

Diastereoselective ritter reactions of chiral cyclic N-acyliminium ions: synthesis of pyrido- and pyrrolo [2,3-d] oxazoles and 4-hydroxy-5-N-acylaminopyrrolidines and 5-hydroxy-6-N-acylaminopiperidines

Pyrido- and pyrrolo[2,3-d]oxazoles can be conveniently prepared in high yield from the Ritter reaction of nitriles and in situ generated chiral cyclic N-acyliminium ions. cis-4-Hydroxy-5-acylaminopyrrolidines and cis-5-hydroxy-6-acylaminopiperidines can be readily obtained by acid hydrolysis of these bicyclic heterocyclic compounds, respectively

Diastereoselective borono-Mannich reactions on cyclic N-acyliminium ions

The addition of boronic acids to five- and six-membered ring N-acyliminium ions has been employed to prepare 5- and 6-substituted 4-hydroxypyrrolidin-2-ones and 5-hydroxypiperidin-2-ones, respectively, in a diastereoselective fashion