N,N-Diethyl-O-sulfamate (OSO2NEt2) has been established as a new directed metalation group (DMG). Its similarity to the established O-carbamate DMG has prompted investigation into its potential as a partner in transition metal-catalyzed cross coupling reactions with aryl organometallics with the intention to develop a new route to contiguously substituted aromatics. Furthermore, aryne formation of ortho-magnesiated O-sulfamates at higher temperatures can be trapped with furan to afford cycloaddition products having substitution patterns difficult to prepare by similar methods. Schumanniophytine is a structurally interesting alkaloid possessing anti-viral activity. Thus far, only a single synthesis has been reported which proceeds in poor yield and offers little opportunity for the synthesis of structurally diverse schumanniophytine derivatives. Herein we report the total synthesis of schumanniophytine by a directed ortho metalation (DoM) – cross coupling strategy using a key directed remote metalation (DreM) step. The synthesis proceeds in 10 steps with 24% overall yield, offering plenty of opportunity for structural variation. Naturally abundant chromone derivatives contain an array of biological activities. The ability to prepare differentially substituted chromones in a rapid manner is of great interest in medicinal chemistry. Reported is a general and divergent synthesis of chromone carboxamides, from easily prepared 2-but-2-ynoyl aryl O-carbamates. The reaction proceeds by carbamoyl translocation and anionic Fries rearrangement followed by Michael addition of the initially generated cumulenolate for which evidence is provided. Further metalation and borylation reactions of the synthesized compounds allow the regioselective construction of polysubstituted chromones. / Thesis (Ph.D, Chemistry) -- Queen's University, 2007-11-30 11:18:51.673

Lithium bis(amido)cuprates are an important class of bimetallic base, which can chemo- and regioselectively metalate aromatic compounds, via directed ortho cupration (DoCu). This thesis begins with an introduction to aspects of the chemistry of organolithium compounds, group 11 organometallic compounds and their lithium 'ate complexes. Examples of such synergic bases are presented and the introduction is concluded with a discussion of lithium bis(amido)cuprate bases, which along with their silver congeners, are the subject of this dissertation. In general, syntheses involve the addition of a lithium amide to a group 11 salt, resulting in the formation of a lithium bis(amido)cuprate or argentate. Structurally focussed work commences with the use of new amide ligands to develop heteroleptic bis(amido)cuprate systems. The reaction of mixtures of lithium amides with CuBr provides a series of novel Lipshutz-type and Gilman cuprates. Interesting structural features are uncovered, which are rationalised in terms of altered steric demands in the newly introduced amide ligands in these systems. CuSCN and CuOCN are investigated as inexpensive and safer alternatives to CuCN in cuprate formation. In the solid state, a series of Lipshutz-type cuprates (TMP)2Cu(SCN)Li2(L) (L = Et2O, THF, THP) are revealed, whose molecular conformations are infuenced by the identity of the Lewis base. However, in benzene solution, in situ conversion of Lipshutz-type to Gilman cuprate is found to occur. Moving to the synthetic setting, derivatisation of chloropyridines is attempted and gives functionalised halopyridines in 51-71 % yield. CuOCN is found to behave quite differently when reacted in the same way as CuSCN, whereby X-ray crystallography reveals structures in which Cu-Li substitution is apparent. The unique reactivity of CuOCN is interpreted with the aid of multinuclear NMR spectroscopy. A new route to Lipshutz-type cuprates is explored by the synthesis of (TMP)2Cu(OCN)Li2(THF) from Gilman cuprate and LiOCN. This avoids Cu-Li substitution. Meanwhile, reaction of lithium N,N-diisopropylamide with CuOCN also avoids metal disorder, to give a novel lithium cuprate-lithium amide adduct. Further advances in our understanding of group 11 'ate complexes are made by introducing silver as a spectroscopically active nucleus in the lithium argentates (TMP)2AgLi and (TMP)2Ag(CN)Li2(THF). In the solid state, these parallel the structures known for Gilman cuprate (TMP)2CuLi and Lipshutz cuprate (TMP)2Cu(CN)Li2(THF), respectively. In solution, NMR spectroscopy reveals features consistent with retention of these structures. Lastly, the formation of mixed Cu-Li aggregates from combining TMPLi and TMPCu in aromatic solvent are investigated. Surprising reactivity is uncovered, in which the aromatic solvent is metalated and incorporated into mixed-metal aggregates. This thesis concludes with a summary of the findings and suggestions for future work, including how the findings presented herein may be transformed into practical improvements to cuprate systems. In particular, the possibility that Gilman cuprate may be activated towards the metalation of aromatic substrates by the addition of sub-stoichiometric or catalytic amounts of a lithium salt additive is explored.

Electrophilic aromatic substitution (EAS) and directed ortho-metalation (DoM) involve the direct substitution of an arene hydrogen. A major drawback involving EAS is the necessity for harsh forcing conditions for the reaction to proceed. Catalysts such as Lewis acids FeBr3 and AICI3 for the introduction of halogens and acyl groups, respectively, are each highly toxic and corrosive. Textbook preparations of aryl iodides classicaly involved the use of iodine and nitric acid. This approach affords only modest yields and does not provide regiospecific substitution of most substituted aromatics because most contain ortho/para directors which afford mixtures of isomers. The novelty of our procedure for the synthesis of the iodinated aromatics is twofold in that regiospecific para-iodination is observed and hydrocarbon media are utilized. Hydrocarbon media are less hazardous and greener than media used for halogenations reported in literature. This procedure always yields derivatives regiospecifically substituted para to an electron donating substituent. Moreover, this method eliminates the need to use hazardous oxidative catalysts. DoM is a reaction regiospecifically substitute an arene hydrogen at the ortho position. The media used in DoM reactions are less hazardous than those required for a variety of EAS reactions. The only problem for this reaction is use of extremely strong bases, alkyllithium reagents, which are known to be air and water sensitive. However, the DoM reaction does eliminate the need to separate ortho/para isomer mixtures so that only a single product is generated. The metalation yields predominantly products regiospecifically substituted ortho-to the direcing metalating group (DMG). With our deficiency catalysis concept and subsequent purificaion methods, relatively pure ortho-lithiated intermediates have been prepared. The study of catalysts/promoters on the derivatization of these intermediates is anticipated to be extremely insightful. For this study, we have shown that highly selective, efficient ortho-lithiation can be achieved by deficiency catalysis utilizing n-BuLi as the only strong metalating base.

The Directed ortho Metalation reaction is described in Chapter 1 of this thesis with particular emphasis on its mechanism and synthetic potential. Chapter 2 contains a review of the DoM (Directed ortho Metalation) of pyridine systems and describes the conditions that allow the one-pot DoM (Directed ortho-Metalation)-Boronation-Suzuki-Miyaura cross coupling of pyridines 2.263a-c, 2.351-2.53 (Table 2.9) bearing several DMGs (Directed Metalation Groups) including the synthetically versatile diethyl amide functionality without incurring into commonly observed self-condensation processes. The method avoids the tedious and uncertain isolation of the intermediate boronic acids while offering rapid access to synthetically valuable arylpyridines (2.354a-s, Table 2.9). Selected aryl pyridine carboxamides were used to demonstrate the DoM-DreM (Directed remote Metalation) nexus that furnishes substituted and isomerically diverse azafluorenones 2.380a-d (Table 2.11) with high regioselectivity. The previous discovery of the anionic O→C -vinyl carbamoyl migration of carbamoyl stilbenes stimulated its application in the total synthesis of natural product isoprekinamycin, bearing the unusual diazo group. Chapter 3 of this thesis describes the efficient synthesis of the key stilbene derivative 3.113 and its structural variations whose conversion to the desired naphthols 3.143, 3.144, 3.153 and 3.169 (Table 3.3) is accompanied by extensive decomposition, thus terminating this approach to isoprekinamycin. A modified approach via Z-3.271 (Scheme 3.54) gave the desired naphthyl carbamate intermediates 3.274 and 3.278 (Schemes 3.55 and 3.56, respectively) whose complex DreM reactions prevented the completion of the synthesis but remain under active investigation in our laboratories. Previous studies of the DoM reaction of aryl tetramethyl phosphorodiamidate have shown that unpractical experimental conditions are necessary, thus limiting synthetic application. Chapter 4 of this thesis describes the results concerning the performance of the tetraethyl phosphorodiamidate DMG under standard DoM and DreM conditions, anionic phospha-Fries rearrangement, 1,4 lateral migration, and Suzuki cross coupling which demonstrate synthetic utility and application in synthetic aromatic chemistry. / Thesis (Ph.D, Chemistry) -- Queen's University, 2008-12-16 14:15:09.695

This thesis details a straightforward synthetic route to the antifungal compound pyrrolnitrin 1.2, along with several analogous halogenated phenylpyrroles. The proposed synthetic protocol involved the Suzuki-Miyaura cross-coupling of appropriately halogenated pyrrole pinacolboronate esters and aryl compounds. In the efforts towards preparing the cross-coupling partners, we report a regiospecific and high yielding synthesis of a 3-chloro pyrrole compound 2.14, its brominated analog 2.16, an iodinated analog 2.17, and the corresponding pinacolboronate ester 2.18. We also report a generalized reaction sequence (lithiation/carboxylation/Schmidt reaction/oxidation) for the preparation of halogenated benzoic acids, anilines and nitrobenzenes. In particular, we synthesized the desired halogenated nitrobenzene coupling partner 3.27 in excellent yield. We were also able to show that the conditions employed in this sequence were mild enough to allow preparation of the 2-bromo-6-iodo compound 3.33. Once the coupling partners were prepared, we developed the optimal conditions for our Suzuki-Miyaura cross-coupling reactions. In doing so, we were able to prepare our target compound 1.2 and several halogenated analogs in good yields. We also prepared brominated and deuterated arylpyrroles 4.27 and 4.28, respectively, for future use in mechanistic studies of the pyrrolnitrin biosynthetic enzymes, PrnB, Prn C and PrnD. This required preparation of the corresponding brominated and deuterated pyrrole pinacolboronate esters 4.24 and 4.26. / Thesis (Master, Chemistry) -- Queen's University, 2009-09-29 13:58:35.186

No description available.