Academic literature on the topic 'Selective electrophilic aromatic substitution'

This thesis investigates the potential of the alkaloid isocryptolepine 16 as a lead compound in antimalarial drug development. Fifteen derivatives of the parent alkaloid were prepared and fully characterised, twelve of which were novel compounds. A select group of compounds were subsequently evaluated for both antimalarial activity and cytotoxicity.Three previously reported synthetic methodologies to the parent alkaloid were initially investigated; wherein two approaches were able to be reproduced or improved. These two synthetic methodologies were subsequently applied to the preparation of derivatives. The first of these methodologies, the Jonckers Method, involved two consecutive palladium catalysed coupling reactions. During the course of these investigations it was found that these two reactions could be combined into a single ‘domino’ reaction resulting in a reduction in the number of steps required to prepare the parent alkaloid. This methodology was then applied to the preparation of both ring-substituted and structural isomers. The second methodology, The Molina Method, involved a benzotriazole-mediated strategy and was applicable to preparing isocryptolepine derivatives with ring substituents on the quinoline ring. Finally a method for selective electrophilic aromatic substitution was developed and applied to the preparation of a further range of halogenated derivatives.Eight of the prepared derivatives were selected for biological evaluation. Antimalarial activity was assessed against a chloroquine sensitive and resistant strain of P. falciparum, whilst cytotoxicity was evaluated against mouse embryonic fibroblasts (3T3 cells). All compounds were found to be more active compared to the parent alkaloid against the chloroquine resistant strain of P. falciparum; specifically 8-bromo-2-chloroisocryptolepine 107 (IC[subscript]50 = 85 nM) and 8-bromo-3-chloroisocryptolepine 105 (IC[subscript]50 = 100 nM) were the most potent. Cytotoxicity evaluations revealed that ring substitution did not enhance cytotoxicity and the most potent antimalarial derivative, 8-bromo-2-chloroisocryptolepine 107 (IC[subscript]50 = 9.01 μM), displayed a 4-fold reduction in cytotoxicity.In conclusion, isocryptolepine 16 and its derivatives have significant potential as antimalarial lead compounds, with many derivatives possessing enhanced bioactivity versus the parent. This study has also identified 8-bromo-2-chloroisocryptolepine 107 to be a very promising lead compound which warrants further biological or pharmaceutical investigation.

Chapter 1 highlights the many advantages of heterogeneous inorganic solids as catalysts, and summarises the various microporous and mesoporous solids that have been employed as catalysts. The synthesis and characterisation of the mesoporous materials that were used in the study are described. Chapter 2 focuses on the nitration of naphthalene. An introduction to nitration is given, and the results of nitration over a range of solids are presented. Unusual dinitronaphthalene product ratios were achieved over Al-MCM-41. Reactions catalysed by heteropoly acid immobilised within the pores of mesoporous materials are also described. Chapters 3 to 6 focus upon the alkylation of naphthalene. Emphasis is placed upon the importance of 2,6-dialkylnaphthalenes (2,6-DAN) as intermediates for the production of high performance engineering plastics, and why there is still significant room for improvement in both 2,6-DAN yield and selectivity. A molecular modelling study of 2,6- and 2,7- di-<I>tert</I>-butylnaphthalene (DTBN) highlighted the potential for achieving selectivity for the 2,6-over the 2,7-isomer. Zeolite H-Mordenite (HM) was the most selective catalyst for 2,6-DTBN, but showed poor activity. Efforts to increase both the 2,6-DTBN yield and selectivity over HM focused upon varying the reaction time; temperature; pressure; solvent; amount of alkylating agent, solvent, and catalyst; Si/Al ratio of the catalyst; and mode of addition. Optimisation resulted in a 60% yield of 2,6-DTBN with a 2,6/2,7 ratio of over 50. <I>tert</I>-Butylation reactions were achieved using mainly <I>tert</I>-butanol as the alkylating agent. The identification of by-products in the <I>tert-</I>butylation reaction has been attempted. Alkylation with other alkylating agents has been attempted, but selectivity for 2,6-DAN was inferior to that achieved in the <I>tert</I>-butylation reaction using <I>tert</I>-butanol.

Thesis (Ph. D.)--University of California, San Diego and San Diego State University, 2006.<br>Title from first page of PDF file (viewed June 7, 2006). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references (p. 280-290).

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 terpene and terpenoid family of compounds is considered to be the largest group of natural products. These compounds not only display great diversity in their structural features but are also known to have a multitude of biological activities including but not limited to anti-bacterial, anti-cancer, anti-inflammatory, and anti-HIV properties. Remarkably, all the terpenoids formed in nature come from two molecules viz. isopentenyl pyrophosphate and its isomer, dimethylallyl pyrophosphate both consisting of just five carbons but assembled in many ways. Nature utilizes highly efficient, enzyme-mediated cascade reactions to transform simple linear molecules to more complex cyclic scaffolds. Cascade or domino reactions are organic chemistry’s most powerful tools that, if executed correctly, mimic the extreme complexity of reactions occurring in nature. Our group has successfully utilized cationic cascade cyclization reactions, to prepare a large library of natural products along with their analogues. It was during the synthesis of one such natural product that it was discovered that a methoxymethyl (MOM) “protecting group” had been transferred within the same molecule. The optimization of this process not only allowed the synthesis of the desired tricyclic framework but also resulted in the liberated MOM group doing an EAS reaction which gave a new C-C bond. This transferred MOM group was further elaborated to different functional groups. Use of the tandem reaction sequence in an attempt to prepare radulanin E has been described. Total syntheses of two chalcone-based analogous meroterpenoids have been successfully completed using the aforementioned sequence. An advanced intermediate for an entire new class of acridine-based schweinfurthins has been elaborated. The results will be discussed in detail.

Bromoarenes are important aromatic building blocks that are commonly used to synthesize various functional compounds in pharmaceutical, agrochemical and related industries.1,2 This great demand for bromoarenes makes their preparation a widely studied area of synthetic organic chemistry. However, further understanding of the reactivity and regiochemistry of aromatic functionalization reactions is still necessary, as much about the secondary substitution and solvent effects remain unknown. Resonance Theory is a widely used theoretical model to predict the regiospecifity and reactivity of the bromination of various aromatic compounds.3 The reactivity and regiospecificity of many substituted aromatic compounds is well explained using resonance theory.4 However, kinetic understanding of the p-bromination of halosubstituted aromatic compounds has not been investigated to the best of our knowledge.5,6In this thesis, the reactivity and regiospecifity of the p-bromination of activated secondary substituted aromatic compounds as well as media effects on the process will be discussed. Synthesizing bromoarenes has been accomplished using many different experimental setups.7-11 N-bromosuccinimide is the most highly utilized electrophilic aromatic brominating agent. Many of the NBS- based aromatic bromination reactions have been reported using strong acids, strong bases, halogenated solvents, nonpolar solvents and polar solvents alike.12 The bromination reactions reported herein were performed using two different solvents, acetonitrile and acetone, to investigate the effects of solvent polarity on p-bromination. Although acetonitrile is one of the most commonly used solvents in the p-bromination of aromatic compounds, acetone has not been investigated.