Reactions of some non-enolisable chloroketones with amide ion and a new synthesis of acridones /|nGuo-shyoung John Chen. -- 260 St. Catharines, Ont. : [s. n.],

This research was directed mainly towards the investigation of the reacti.ons of· substituted chlorobenziophenones under strongly basi,c conditions. The work 'can be divided into two main sections. The Introduction deals mainly with historical studies on aryne chemistry and the Haller-Bauer reaction. Secti.on I i.s concerned with syntheses of 2-benzamido-2'chlorobenzophenone and 2-benzamido~3'-chlorobenzophenone,and with thei,r respective reactions wi.th potassium amide in ammonia. o-Chlorophenylacetic acid was converted to the acid chloride and then by Friedel-Craftsreaction with benzene to w-(o-chlorophenyl)acetophenone. Reaction wi.th phenylhydrazine and Fischer cyclization gave 3- (0chlorophenyl)- 2-phenylindole, which was ozonized to 2-benzamido-2'chlorobenzophenone. The isomeric 3' -chlor,..o ke: tone was similarly synthesised from m-chlorophenylacetic acid. Both the 2'- and 3' -ch.loroketones gave N-benzoylacridone on treatment with potassium amide in ammonia; an aryne mechanism is involved for the 3'-chloroketone but aryne and nucleophilic substitution mechanisms are possible for the 2'-chloroketone. Hydrolysis of the 2'- and 3'-chloroketones gave 2-amino-2'chlorobenzophenone and 2-amino-3'-chlorobenzophenone respectively. A second new acridone synthesis is given in the Appendix involving reactions of these two ketones with potassium t-butoxide in t-butylbenzene. i Section 2 deals with the investigation of the reaction of some tricyclic ch1orobenzophenones with potassium amide in liquid ammonia. These were 1-ch1orof1uorenone; which was pr~pared in several steps from f1uoranthene, and 1- and 2-ch1oroanthraquinones. 1-Ch1orof1uorenone gave 1-aminof1uorenone ; 1-ch1oroanthraquinone gave 1- and 2-aminoanthraquinones; 2-ch1oroanthraquinone was largely recovered from the attempted reaction.

The nucleophillic substitution of various chloroanthraquinones of their possible rearrangement via aryne intermediates

The work in this thesis deals mainly with nucleophilic substitution of chloroanthraquinones as a route to various starting materials which might rearrange, via aryne intermediates to afford fused-ring heterocy1ic carboxylic acids. 1-Amino-5-chloroanthraquinone was successfully prepared by reacting 1,5-dichloroanthraquinone with sodium aZide in ref1uxing dimethylsulfoxide (DMSO). It could also be prepared from the same starting material by reaction with ammonia (gas) in DMSO in the presence of potassium fluoride. Treatment of l-amino-5-chloroanthraquinone with potassium amide in liquid ammonia or with potassium t-butoxide in t-butylbenzene returned mainly starting material, although in the latter case some 1-amino-5-hydroxyanthraquinone was also isolated. 1-Hydroxy-5-chloroanthraquinone was ultimately prepared by diazotization of the amino-analog. It was recovered almost quantitatively after treatmenu'with potassium amide in liquid ammonia. The reaction with potassium t-butoxide in t-buty1benzene was anomalous and gave 1-hydroxyanthraquinone as the only iso1able product. Acridines were successfully prepared by the action of 70% sulfuric acid on 1,5-bis(p-toluidino)-anthraquinone and 1-p-toluidino-5- ch10roanthraquinone, and in the latter case, cleavage to give an acridinecarboxylate was attempted. Substituted anthraquinones reacted with sodium azide in sulfuric acid to give azepindiones by -NH insertion. Methods for separating and identifying isomeric mixtures of these compounds were examined. Attempted decarbonylation of selected azepindiones to give acridones gave mainly what were thought to be amino-benzophenone derivatives. Chloroanthraquinones were found to react with hexamethylphosphoramide (HMPA) to give mixtures of the dimethylamino- and methylaminoderivatives. Under the same conditions halogeno-nitrobenzenes and nitrophenols were substituted to give the appropriate dimethyl aminobenzenes, except in two cases. 3-Chloronitrobenzene reacted anomalously to give a small amount of 3,3'-dichloroazobenzene and a trace of 4-dimethylamino-nitrobenzene. Pentachlorophenol reacted to give a pentachlorophenylphosphorodiamidate in good yield.

The suppression of the Haller-Bauer scission for synthetic purposes /|nby S. M. Vines. -- 260 St. Catharines, Ont. : [s. n.],

A number of 2-chlorobenzophenones, containing electron releasing groups (e.g. hydroxy, thiomethoxy and methoxy) in the 4' - position, were prepared by the Friess rearrangement, or the Friedel-Crafts reaction. These ketones, when treated with potassamide in liquid ammonia, underwent partial Haller-Bauer scission, unlike 2-chlorobenzophenone which is known to undergo complete scission. Under similar conditions 4-nitrobenzophenone also underwent partial scission, but the main reaction in this case was nucleophilic amination of the nitro containing ring. This amination reaction was shown not to be a useful general reaction for aromatic nitro compounds. 3-Methylxanthone was then prepared by treatment of 2- and 3- chloro-2'-hydroxy-5'-methylbenzophenone with . little, if any, attendant scission. The corresponding 2fluoro- compound also gave the xanthone, but as the 3-fluoro compound did not, it was concluded that the 2-fluoro compound reacted through a nucleophilic substitution mechanism, rather than the benzyne mechanism invoked for the chloro and bromo compounds. 3-Methylthioxanthone was synthesised by treatment of methyl 4-tolyl sulphide and 2-chlorobenzoyl chloride with aluminum chloride in carbon disu1phide, followed.by heating. This compound was also prepared by treatment of 3-chloro-2'thiomethoxy- 5'-methylbenzophenone with potassamide in liquid ammonia.

A G. C./M. S. study of the reaction and decomposition products of pentafluorophenyl-grignard and lithium reagents

Decomposition and side reactions of, and the synthetic use of, pentafluorophenylmagnesium bromide and pentafluorophenyllithium have been investigated using G,C9/M.S, techniques• Their reactions with reagents such as CgF^X (X - H, F, CI, Br, 1), C6F4X2 (X - H, CI)f C6F3C13, C6H6. (CgX5)3P (X = H, F), (C6X5)3P=0 (X = H, F), (CgX5)Si (CH3)3 (X = H, F) and (CH0K SiCl , n = 1,2, in ether or ether/n-hexane were studied• In addition to the principal reaction of synthetic use, namely the replacement of a halogen by a pentafluorophenyl group, two types of side reactions were observed* These were (i) intermolecular loss of LiF via a nucleophilic substitution, and (ii) intramolecular loss of LiF, followed by the addition of either inorganic salts such as lithium or magnesium halides, or organometal compounds such as organolithium or organo-Grigaard* G.C«/M.S. techniques were routinely employed to study complicated reaction mixtures. Although mass spectrometry alone has disadvantages for the identification of isomers, deduction of the most probable pathway often helps overcome this problem.

Synthesis of Chiral Benzimidazolylidenes from 1,10-Phenathrolines and 1,10-Phenathroline-2,9-dione /

A^-heterocyclic carbenes (NHCs) have become the focus of much interest as ancillary ligands for transition metal catalysts in recent years. Their structural variability and strong cy-donation properties have led to the preparation of demonstrably useful organometallic catalysts. Among the three general structural types of NHCs (imidazolylidenes, imidazolinylidenes, and benzimidazolylidenes), benzimidazolylidenes are the least investigated because of the limitation of current synthetic approaches. The preparation of chiral analogues is even more challenging. Previously, our group has demonstrated an alternative approach to synthesizing benzimidazolylidenes with a tetracyclic framework in three steps from 1,10-phenanthroline. This thesis is focused on approaches to chiral benzimidazolylidenes derived from substituted 1,10-phenanthrolines. A key step in the preparation of these ligands involves a reduction of the pyridyl rings in 1,10-phenanthrolines. Chirality can be introduced to phenanthrolines before, during, or after the reduction as illustrated by three approaches: 1) de novo construction of the phenanthroline from chiral ketones with endo and exo faces to provide a degree of diastereoselectivity during subsequent reduction; 2) introduction of substituents into the 2- and 2,9- position of phenanthroline by nucleophilic aromatic substitution, followed by a reduction-resolution sequence; and 3) use of the protected octahydrophenanthroline as a substrate for chiral induction a to nitrogen.

Diastereoselective Lithiation-Substitution of N-Silyl-Protected-(S)-Tetrahydro-1H-pyrrolo[1,2-c]imidazole-3(2H)-ones and Applications of Their Derivatives

This thesis describes a method involving the preparation of an L-proline-derived imidazolone protected with an N-triethylsilyl group that undergoes diastereoselective lithiation followed by electrophile quench to give C5-substituted products with syn stereochemistry. The N-silylated derivatives may be more easily N-deprotected as compared to previous N-t-Bu analogues to give secondary ureas. These may serve as precursors to N-phenyl chiral bicyclic guanidines or as NHC precursors for synthesis of corresponding complexes.

Diastereoselective Lithiation-Substitution of N-Silyl-Protected-(S)-Tetrahydro-1H-pyrrolo[1,2-c]imidazole-3(2H)-ones and Applications of Their Derivatives

This thesis describes a method involving the preparation of an L-proline-derived imidazolone protected with an N-triethylsilyl group that undergoes diastereoselective lithiation followed by electrophile quench to give C5-substituted products with syn stereochemistry. The N-silylated derivatives may be more easily N-deprotected as compared to previous N-t-Bu analogues to give secondary ureas. These may serve as precursors to N-phenyl chiral bicyclic guanidines or as NHC precursors for synthesis of corresponding complexes.

Studies of nucleophilic attack on tris (pentafluorophenyl) phosphine and its oxides

The reaction of tris(pentafluorophenyl)phosphine [5] with the nucleophiles dimethyl formamide (DMF), hexamethylphosphoric triamide (HMPA), diethyl formamide (DEF), hexaethylphosphoric triamide (HEPA), hydrazine, N,N-dimethyl hydrazine (in presence and/or absence of KF), phenylhydrazine, ammonium hydroxide, formamide, aniline, sodium hydrogen sulfide, and hexaethylphosphorous triamide was investigated. The reaction of [5] with DMF and HMPA gave the same product, namely tris-[4-(N,N-dimethylamino)-2,3,5,6-tetrafluorophenyl]phosphine [12] but in higher yield in the case of HMPA. Compound (5] also reacted with DEF to give tris[4-(N,N-diethylamino)-2,3,5,6-tetrafluorophenyl] phosphine [14]. When [51 was treated with HEPA, it gave a mixture of bis(pentafluorophe~yl)-(N,N-diethylamino-tetrafluorophenyl)phosphine, pentafluorophenyl-bis-(N,N-diethylamino-tetrafluorophenyl)phosphine and tris (N,N-diethylamino-tetrafluorophenyl)phosphine. Treatment of [5] with aqueeus hydrazine solution in excess ethanol gave tris(4-hydrazo-2,3,4,6-tetrafluorophenyl)phosphine [1s1 in high yield while reaction with aqueous hydrazine led to C-P cleavage and production of tetrafluorophenyl hydrazine. With N,N-dimethyl hydrazine, [5] gave tris(4-N,N-dimethylhydrazine-2,3,5,6-tetrafluorophenyl) phosphine {20j. The latter could be obtained in higher yield and shorter reaction time, by the addition of KF. The reaction of compound {51 with phenylhydrazine in THF gave bis(pentafluorophe~yl)-4-S-phenylhydrazino- 2,3,5,6-tetrafluorophenyl phosphine [22] in low yield. Reaction of [5] with ammonium hydroxide in THF at high pressure in the presence of KF gave tris-~4-amino-2,3,5,6-tetrafluorophenyl)phosphine [25]. Similarly, formamide led to a mixture of (C6F4NHZ)3P, (C6F4NHZ)ZPC6FS, (C6F4NHZ)ZPC6F4NHCHO, and C6F4NHZP(C6Fs)(C6F4NHCHO). When [5] was treated with aniline, a mixture of mono-, di-, and tri-substituted products was obtained. Sodium hydrogen sulfide in ethylene glycol/ pyridine led to C-P cleavage and the isolation of pentafluorobenzene and tetrafluorothiophenol. Reaction of [5] and its oxide [35] with different alkoxides in the corresponding alcohols led mainly to C-P bond cleavage products, with the exception of one case where sodium methoxide was used in ether, and which led to tris-(4-methoxy-2,3,9,6-tetrafluorophenyl)phosphine [37]. On the basis of various spectroscopic data, it was concluded that the para position in compound [5] was generally the favoured site of attack.

Stereoselective synthesis of 5-substituted pyrrolo[1,2-c]imidazol-3-ones. Access to aldosterone synthase inhibitors and chiral precatalysts

Compounds containing the pyrrolidine moiety are key substructures of compounds with biological activity and organocatalysts. In particular, annulated chiral pyrrolidines with alpha stereogenic centers have aldostereone synthase inhibition activity. In addition, 5-substituted pyrroloimidazol(in)ium salts precursors to N-heterocyclic carbene (NHC) precatalysts are rare due to a lack of convenient synthetic routes to access them. In this thesis is described a rapid synthesis of NHC precursors and a possible route to 5-substituted pyrroloimidazole biologically active compounds. The method involves the preparation of chiral saturated and achiral unsaturated pyrrolo[I,2- c]imidazol-3-ones from N-Cbz-protected t-Butyl proline carboxamide. The resulting starting materials may be used to prepare the target chiral annulated imidazol(in)ium products by a two-step sequence involving first stereoselective lithiation-substitution, followed by POCh induced salt formation.

Stereoselective synthesis of substituted hexahydro-3a,4a-diazacyclopentaphenanthren-4-ones and aminoferrocenes

This thesis explored the development of several methodologies for the stereoselective construction of ligand frameworks and some of their applications. The first segment concerns the application of an enantioselective lithiation at an Sp3_ hybridized position adjacent to nitrogen by means of the widely used and typically highly effective enantioselective lithiation with ( -)-sparteine. This investigation was intended to develop a method to install chirality into a system that would be converted into a family of diaminoylidenes for use as phosphine mimics in transition metal catalysis or as nucleophilic reagents. Molecular modeling of the system revealed some key interactions between the substrate and (-)-sparteine that provided general insight into the diamine's mode of action and should lend some predictive value to its future applications. The second portion focuses on the development of methods to access 1,2- disubstituted aminoferrocenes, an underexplored class of metallocenes possessing planar chirality. Two routes were examined involving a diastereoselective and an enantioselective pathway, where the latter method made use of the first BF3-mediated lithiation-substitution to install planar chirality. Key derivatives such as 1,2- aminophosphines, made readily accessible by the new route, were evaluated as ligands for Pd(II), Pt(II) and Ir(I). These complexes show activity in a number of transformations with both achiral and prochiral substrates. Optimization experiments were conducted to prepare enantiomerically enriched 2-substituted-I-aminoferrocenes by direct asymmetric lithiation of BF3-coordinated tertiary aminoferrocenes. A predictive computational model describing the transition state of this reaction was developed in collaboration with Professor Travis Dudding's group (Department of Chemistry, Brock University). The predicted stereochemistry of the process was confirmed by single-crystal X-ray analysis of a 2-phosphino-l-dimethylaminoferrocene derivative. Enantiomerically pure samples of the aminophosphine ligands derived from this new process have given promising preliminary results in the enantioselective hydrogenation of prochiral alkenes and warrant further stUdy in metal-mediated catalysis.

Tetrathiafulvalene and 2,2'-Bipyridine: Bridging both Worlds in the Pursuit of Novel Molecular Materials

The preparation and characterization of two families of building blocks for molecule-based magnetic and conducting materials are described in three projects. In the first project the synthesis and characterization of three bis-imine ligands LI - L3 is reported. Coordination of LI to a series of metal salts afforded the five novel coordination complexes Sn(L4)C4 (I), [Mn(L4)(u-CI)(CI)(EtOH)h (II), [CU(L4)(u-sal) h(CI04)2 (sal = salicylaldehyde anion) (III), [Fe(Ls)2]CI (IV) and [Fe(LI)h(u-O) (V). All complexes have been structurally and magnetically characterized. X-ray diffraction studies revealed that, upon coordination to Lewis acidic metal salts, the imine bonds of LI are susceptible to nucleophilic attack. As a consequence, the coordination complexes (I) - (IV) contain either the cyclised ligand L4 or hydrolysed ligand Ls. In contrast, the dimeric Fe3+ complex (V) comprises two intact ligand LI molecules. In. this complex, the ligand chelates two Fe(III) centres in a bis-bidentate manner through the lone pairs of a phenoxy oxygen and an imine nitrogen atom. Magnetic studies of complexes (II-V) indicate that the dominant interactions between neighbouring metal centres in all of the complexes are antiferromagnetic. In the second project the synthesis and characterization two families of TTF donors, namely the cyano aryl compounds (VI) - (XI) and the his-aryl TTF derivatives (XII) - (XIV) are reported. The crystal structures of compounds (VI), (VII), (IX) and (XII) exhibit regular stacks comprising of neutral donors. The UV -Vis spectra of compounds (VI) - (XIV) present an leT band, indicative of the transfer of electron density from the TTF donors to the aryl acceptor molecules. Chemical oxidation of donors (VI), (VII), (IX) and (XII) with iodine afforded a series of CT salts that where possible have been characterized by single crystal X -ray diffraction. Structural studies showed that the radical cations in these salts are organized in stacks comprising of dimers of oxidized TTF donors. All four salts behave as semiconductors, displaying room temperature conductivities ranging from 1.852 x 10-7 to 9.620 X 10-3 Scm-I. A second series of CT salts were successfully prepared via the technique of electrocrystallization. Following this methodology, single crystals of two CT salts were obtained. The single crystal X-ray structures of both salts are isostructural, displaying stacks formed by trimers of oxidized donors. Variable temperature conductivity measurements carried out on this series of CT salts reveal they also are semiconductors with conductivities ranging from 2.94 x 10-7 to 1.960 X 10-3 S em-I at room temperature. In the third project the synthesis and characterization of a series of MII(hfac)2 coordination complexes of donor ligand (XII) where M2+ = Co2+, Cu2+, Ni2+ and Zn2+ are reported. These complexes crystallize in a head-to-tail arrangement of TTF donor and bipyridine moieties, placing the metal centres and hfac ligands are located outside the stacks. Magnetic studies of the complexes (XV) - (XVIII) indicate that the bulky hfac ligands prevent neighbouring metal centres from assembling in close proximity, and thus they are magnetically isolated.