Academic literature on the topic 'Heterocyclic chemistry ; Heterocyclic compounds'

This thesis describes the preparation and characterisation of a number of homochiral coordination and metallosupramolecular assemblies. These species were formed from the reaction of chiral pyridine and quinoline containing ligands and metal ions. The combination of traditional coordination chemistry and supramolecular interactions led to a range of polymeric and network structures being formed. The ligands used in this thesis can be divided into two broad categories: alkaloids and ligands derived from them, and amino acid-based ligands. In the first category three new ligands were synthesized, and a variety of routes towards alkaloid-based homochiral ligands were investigated. The second category focused on three ligand motifs, and resulted in the preparation of 16 ligands. These two categories of ligands were reacted with a range of metal salts to investigate their coordination and supramolecular chemistry. The structure of twenty complexes was determined by single crystal X-ray crystallography. The complexes had a range of structures, with discrete and polymeric species being formed. Hydrogen bonding was an important feature in the supramolecular chemistry of the complexes, playing a different role in different series of complexes. Two chiral coordination polymers and one chiral coordination network were synthesized. All three of these structures possessed directionality to some degree: in the coordination network and one of the polymers the directionality is counterbalanced by the opposite directionality being present in the crystal, while the second coordination polymer is generated by the screw axis present and has a high degree of overall directionality.

The thesis entitled "Studies on N-Hetero cyclic Compounds: (a) Reaction of 5,6,7,8-Tetrahydroisoquinolines with Vilsmeier Reagent and (b) Amide Induced in situ Alkylation of 5,6-Dihydroisoquinolines" is presented in two parts. Part I involves a study of the Vilsmeier reaction of 4-cyano-1,3-dihydroxy-5,6,7,8 tetrahydroisoquinoline derivatives, while Part II concerns the in situ alkylation of l-alkyl-4-cyano-3-methoxy-5,6- dihydroisoquinolines in presence of KNH2/liq.NH3.

More than 11 million people worldwide are diagnosed with cancer every year. New cancer drugs are required that are more effective and selective. Nitrogen mustard alkylating agents crosslink DNA inhibiting transcription and replication. Use of the mustard pharmacophore as part of a macrocycle allows metal complexation and produces a prodrug. Hypoxic tumour cells have increased concentrations of reductase enzymes which could lead to reduction of the complex in situ and release of a cytotoxic drug. Human African Trypanosomiasis is commonly known as Sleeping Sickness and affects over 36 countries of sub-Saharan Africa. It is transmitted to humans by the tsetse fly which carries the parasitic subspecies Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense. Any compounds synthesised would also be tested to assess their potential as anti-parasitic agents. Parker synthesised a range of polyazamacrocycles. Testing of compound A in vitro gave highly efficient DNA crosslinking activity. Copper complexes were formed of the macrocycles and B was found to be 24 times more toxic against hypoxic cells than oxic cells thus exploiting tumour hypoxia and creating a selective drug. Jones synthesised a range of oxaazamacrocycles such as C which when tested in vitro exhibited comparable cross-linking activity to the azamacrocycles although it proved impossible to synthesise the corresponding copper complexes. It was decided to vary the leaving group on the alkylating arms to see if the DNA crosslinking results could be improved. Eight carbamates and the corresponding copper complexes were synthesised. The R-groups were alkyl and aromatic. Anti-cancer DNA crosslinking and hypoxia selectivity results were disappointing however, a number of compounds displayed significant activity when tested against T. brucei. A range of thiaazamacrocycles would complete the set of heteroatom-containing macrocycles (N, O, S) and might produce good DNA crosslinking results. It might also be possible to synthesise the corresponding copper complexes producing prodrugs. Six thiaazamacrocycles were synthesised and 2-hydroxyethyl arms were attached. However it proved impossible to isolate the desired alkylating agents with the 2-chloroethyl arms. In the body, the p53 protein activates the transcription of specific genes. In healthy cells, the levels of p53 have to be kept to a minimum to allow the normal running of the cell, e.g. growth and replication. This function is carried out by the HDM2 protein, which forms an auto-regulatory feedback loop with p53. In some tumours, the p53 function is disrupted due to genetic mutations of p53. However other tumours possess ‘wild type’ p53 – this type of p53 has lost the ability to respond to oncogenic stress due to over-expression of HDM2. Drugs that inhibit HDM2 should cause stabilisation of p53 and induce apoptosis in cancer cells. A small library of 5-deazaflavins were synthesised and biologically tested producing some interesting biological results.

Tetrazolinones, thiatriazole 1-oxides and meso-ionic oxatriazoles were investigated as sources of free radicals. Mono-substituted tetrazolinones decomposed at their melting points. Nitrosation and nitration of the tetrazolinone ring was unsuccessful, although alkoxyalkylation of the ring took place in ether in the presence of nitrosomium and nitronium tetrafluoroborate. The tetrazolinone ring was photolytically unstable, and both eliminated nitrogen and cycloreverted. γ-irradiation of the naphthyl deivative caused cleavage of the nitrogen-hydrogen bond to give a radical which was identified by spin trapping and esr spectroscopy. Thiatriazolyl radicals were generated from thiatriazol-1-ium salts by reduction over sodium metal. Deuterium and nitrogen-15 labelled diphenylthiatriazolium salts were prepared in the reaction between thiatriazole 1-oxides and phosphorus pentachloride or pentabromide. This allowed an unambiguous assignment of the nitrogen and hydrogen hyperfine coupling constants in the esr spectrum of the unlabelled thiatriazolyl radical. X-ray crystallographic analysis was carried out on single crystals of 2,4-diphenyl-2,5-dihydro-1,2,3,5-thiatriazol 1-oxide and 2,4-diphenyl-2H-1,2,3,5-thiatriazol-1-ium bromide. Meso-ionic oxatriazolones were relatively stable to thermolysis, whereas oxatriazolimines decomposed at their melting points. The oxatriazolones decomposed on photolysis via two mechanistic pathways, while the oxatriazol-imines were resistant to photolysis. Radicals were generated by γ-irradiation and oxidation via decomposition of the heterocyclic ring. Electrochemical reduction of nitrophenyl derivatives allowed an investigation of radicals in which the heterocyclic ring was remote from the radical centre. Photochemical reaction between the nitrophenyl derivatives of the oxatriazole and tetrahydrofuran produced oxy-nitroxide radicals which were realatively long-lived and in which the heterocyclic ring was intact. The rates of hydrolysis and crystal structures of three diacetylazolinones, including diacetyltetrazolinone were investigated with the aim of determining whether a correlation existed between bond lengths and reactivity. The relative rates of hydrolysis were found to be independent of the bond lengths. However a correlation was found between the rates of hydrolysis and the acidity of the unsubstituted azolinones.

The main aim of this project was to develop new reagents capable of exchanging selenium for oxygen under mild conditions, to obtain new carboselenaldehyde (1) and selone (2) compounds. Phenylphosphonoselenoic dichloride (3) was prepared as a solution in xylene. It was reacted with (1,2-dithiol-3-ylidene)carbaldehydes and indolizine-3-carbaldehydes to afford 1,6aλ4-dithia-6-selena-pentalenes (5) and indolizine-3-carboselenaldehydes (6), respectively. The indolizine-3-carbaldehydes had previously been prepared from the corresponding indolizines, in turn prepared from the appropriate pyridinium bromide salts. CHSe(5)(6)Phenylphosphonoselenoic dichloride (3) was also reacted with several other carbonyl compounds. Reactions with N,N.-dimethyl- fonnamide, 5-phenyl-3H-1,2-dithiol-3-one, 2,6-dimethyl-4H.-pyran-4-one, 4-hydroxypyridine, 1-methylpyrrolidin-2-one, hexeihydro-2H-azepin-2-one, and 2,4,6-cycloheptatrien-1-one met with varied success, and only N,N-dimethylselenoformamide (7), 5-phenyl-3H-1,2-dithiole-3-selone (8), and 2,6-dimethy1-4H-pyraxi-4-selone (9) were obtained.(8)(9)The presence of a stabilising substituent was therefore required, and was introduced as a tungsten pentacarboiyl species. Pentacarbon-yl(indolizine-3-carboselenaldehyde-Se) tungsten(0) (10) and penta-carbonyl(2,4,6-cycloheptatriene-1-selone-Se)tungsten(0) (11) were obtained from the reaction of the corresponding oarboryl compounds with phenylphosphonoselenoic dichloride (3) in the presence of tetra- ethylanunonium iodopentacarbonyltungstate(0).The reagent (4) was prepared from the reaction of chlorodlphenyl- phosphine and tetramethylammonium selenocyanate, and was reacted in situ with indolizine-3-carbaldehydes to produce not only indolizine-3-carboselenaldehydes (6), but also compounds which were proposed on the strength of spectral and analytical evidence as being members of the novel 3-(indolizin-3-yl)-2,5-dihydro-2-selenoformyl-1,2,4-selena- diazole-5-selone (12) system.

Baylis-Hillman reactions using various aromatic aldehydes, activated alkenes and catalysts have been used to: - access an extensive range of poly-heterocyclic products;explore chemoselectivity; and optimise reaction efficiency. Chromone-3-carbaldehydes and chromone-2-carbaldehydes, prepared via Vielsmeier-Haack and Kostanecki-Robinson methodology, respectively, have been used as Baylis-Hillman substrates with four different catalysts, viz., 1,4-diazabicyclo[2.2.2]octane (DABCO), 3-hydroxyquinuclidine (3-HQ), imidazole and N’,N’,N’,N’- tetramethylpropanediamine (TMPDA), and with methyl vinyl ketone (MVK), methyl acrylate, cyclic enones (2-cyclohexen-1-one, 2-cyclopenten-1-one and chromones) as activated alkenes. Reactions of the chromone- -carbaldehydes with MVK afforded dimeric Baylis-Hillman adducts when catalyzed by DABCO but when the same reactions were repeated using 3-HQ as catalyst, the dimeric products were accompanied by tricyclic Baylis-Hillman adducts. Use of excess MVK, however, led to mixtures of the normal Baylis-Hillman adducts and the tricyclic adducts – interestingly, with the apparent absence of the dimeric products. While reactions of chromone-3-carbaldehydes with methyl acrylate afforded the normal Baylis-Hillman adducts, the chromone-2- carbaldehydes produced, instead, rearrangement products, consistent with an earlier, single observation. Reactions of 2-nitrobenzaldehydes with cyclic enones using imidazole as catalyst afforded the normal Baylis-Hillman adducts, reductive cyclisation of the 2-cyclohexen-1- one and 2-cyclopenten-1-one adducts, using acetic acid and iron powder, afforded the corresponding quinoline erivatives. Treatment of cyclic enones with pyridine-2-carbaldehydes and quinoline-2-carbaldehydes using TMPDA as catalyst generally gave the expected Baylis-Hillman adducts. However, indolizine derivatives were isolated directly from Baylis-Hillman reactions involving pyridine-2-carbaldehydes and 2-cyclohexen-1-one. The remaining Baylis-Hillman adducts were cyclized to the corresponding indolizines by treatment with acetic anhydride both under reflux and under microwave-assisted conditions, the latter approach providing remarkably rapid and efficient access to the polycyclic products. Computer modelling studies have been conducted on selected polycyclic products at the Molecular Mechanics (MM), Quantum Mechanical (QM) and Density Functional (DFT) levels. The theoretical results have been used to calculate UV, IR and NMR absorption data, which have been compared, in turn, with the experimental spectroscopic data. Use has also been made of the estreNova NMR prediction programme and, generally, good agreement has been observed between the predicted and experimental spectroscopic data.

The reaction of salicylaldehyde with various activated alkenes, viz., methyl vinyl ketone, ethyl vinyl ketone, phenyl vinyl sulfone, phenyl vinylsulfonate, acrolein and acrylonitrile, under Baylis-Hillman conditions, has been found to proceed with the chemoselective formation of chromene derivatives. The reaction conditions have been optimised and chromene derivatives have been obtained in isolated yields up to 87 %. The generality of the reaction, using 1,4-diazabicyclo[2.2.2]octane (DABCO), as the catalyst, and a heterogeneous (chloroform-water) solvent system, has been established using a range of salicylaldehyde derivatives,. including 2-hydroxynaphthaldehyde. The formation of chromene derivatives, under these conditions, has been assumed to proceed via an initial, Baylis-Hillman reaction, followed by cyclisation involving intramolecular conjugate addition, and subsequent dehydration. Evidence supporting this sequence has been obtained from the isolation ofBaylis-Hillman products from reactions involving the use of tertbutylclimethylsilyl-protected salicylaldehyde, 4-hydroxybenzaldehyde and tert-butyl acrylate as substrates. The potential of the ''Baylis-Hillman zwitterion" to participate as a donor species in Michael-type addition reactions has been explored and a series of climeric products has been isolated. The Baylis-Hillman methodology has also been successfully extended to the synthesis of sulfurcontaining heterocyclic systems, and a range of 3-substituted thiochromenes has been obtained in moderate yields, using 2,2'-dithiobenzaldehyde and various activated alkenes in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as catalyst. The electron-impact mass spectra of selected chromene and thiocbromene derivatives have been investigated permitting comparison of the fragmentation of the oxygen- and sulfur-containing analogues. In a study directed at the synthesis of potential HIV -1 protease inhibitors, chromene- and thiocbromene-containing analogues of the clinically useful drug, ritonavir, have been prepared. Thiochromene and chromene derivatives were converted to the corresponding 3 -carboxylic acids and coupled with a specially prepared, hydroxyethylene dipeptide isostere to afford ritonavir analogues containing cbromene and thiochromene termini in ca. 60% yield.

The thesis reports the first examples of Reissert compounds prepared from five-membered ring heterocycles. The method utilises trimethylsilyl cyanide as the key reagent in a single phase non-aqueous medium. Previous attempts to synthesise such compounds have failed because, under the conventional two phase conditions, the reaction either does not proceed or ring opening of the heterocycle occurs. Reaction of benzothiazole with an acid chloride (aliphatic, aromatic or chloroformate) and trimethylsilyl cyanide in dichloromethane has been shown to give rise to 3-acyl-2-cyano-2,3-dihydrobenzothiazoles. Eight such five-membered ring Reissert compounds have been prepared, mostly in yields exceeding 70%. The mechanistic involvement of trimethylsilyl cyanide is discussed. The novel Reissert compounds have been shown to be versatile intermediates for the further modification of the starting heterocycles.