SYNTHESIS OF SUBSTITUTED AROMATIC COMPOUNDS

The goal of chemical synthesis is preparation of a desired compound in high yield, with minimal formation by-products. The synthesis of aromatic compounds using starting materials with a meta-direcring group meets these criteria. For example, we can the convert benzoic acid to -bromobenzoic acid in one step by treating benzoic acid with bromine and iron(III) bromide. The product is a solid (mp 155 °C), which we can separate from the small amounts of ortho- and para-substituted isomers by recrystallization. 

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Aryl diazonium ions prepared by nitrous acid diazotization of primary arylamines are substantially more stable than alkyl diazonium ions and are of enormous synthetic value Their use m the synthesis of substituted aromatic compounds is described m the following two sections... 

The versatility of ArTlXj compounds as intermediates for the synthesis of substituted aromatic compounds has been substantially extended by the observation that the aryl-thallium bond is extremely labile photochemically. The resulting aryl radical can then be captured by appropriate reagents (see below) to give substituted aromatic compounds. A remarkable feature of these photochemical conversions of ArTlXj compounds to substituted aromatics is that, as before, the new substituent always enters the ring at the position to which thallium was originally attached. 

Elimination of nitrogen from Diels-Alder adducts of certain heteroaromatic rings has been useful in the synthesis of substituted aromatic compounds.224 Pyridazines, triazines, and tetrazines react with electron-rich dienophiles in inverse-electron-demand cycloadditions. The adducts then rearomatize with loss of nitrogen and the dienophile substituent.225... 

The overall reaction is the substitution of an electrophile (E+) for a proton (H+) on the aromatic ring electrophilic aromatic substitution. This class of reactions includes substitutions by a wide variety of electrophilic reagents. Because it enables us to introduce functional groups directly onto the aromatic ring, electrophilic aromatic substitution is the most important method for synthesis of substituted aromatic compounds. 

Electrophilic Aromatic Substitution Reactions. Friedel-Crafts alkylation, acylation, and the Vilsmeier-Haack formylation, shown below, are excellent reactions for the synthesis of substituted aromatic compounds. 

These -condensation products are useful in organic synthesis. For example, the vinylsilane portion of the molecule can be used as an internal nucleophile in cyclization reactions, as demonstrated in the synthesis of substituted aromatic compounds (eq 3). They can also be used as lactone precursors (eq 4), as demonstrated in the synthesis of the steroidal IT-spiro-y-lactone (2). ... 

The ability to plan a sequence of reactions in the right order is particularly valuable in the synthesis of substituted aromatic rings, where the introduction of a new substituent is strongly affected by the directing effects of other substituents. Planning syntheses of substituted aromatic compounds is therefore an excellent way to gain confidence using the many reactions learned in the past few chapters. 

In recent years, the importance of aliphatic nitro compounds has greatly increased, due to the discovery of new selective transformations. These topics are discussed in the following chapters Stereoselective Henry reaction (chapter 3.3), Asymmetric Micheal additions (chapter 4.4), use of nitroalkenes as heterodienes in tandem [4+2]/[3+2] cycloadditions (chapter 8) and radical denitration (chapter 7.2). These reactions discovered in recent years constitute important tools in organic synthesis. They are discussed in more detail than the conventional reactions such as the Nef reaction, reduction to amines, synthesis of nitro sugars, alkylation and acylation (chapter 5). Concerning aromatic nitro chemistry, the preparation of substituted aromatic compounds via the SNAr reaction and nucleophilic aromatic substitution of hydrogen (VNS) are discussed (chapter 9). Preparation of heterocycles such as indoles, are covered (chapter 10). 

The Friedel-Crafts reaction is one of the most important and versatile tools for the formation of carbon-carbon bonds in the synthesis of substituted aromatic and heteroaromatic compounds present in numerous natural products and drugs. Catalytic asymmetric variants using either metal complexes or organic molecules attracted considerable attention over the last few years. 

Next, three different mechanisms for nucleophilic substitutions on aromatic rings are presented. These are followed by several other reactions that are useful in synthesis because they interconvert groups attached to aromatic rings. Finally, the use of combinations of all of these reactions to synthesize a variety of substituted aromatic compounds is discussed. 

Alkali metals in liquid ammonia in the presence of an alcohol reduce aromatic systems to 1,4-cyclohexadienes. These can be further elaborated into a host of derivatives. The availability of a wide variety of substituted aromatic compounds, either commercial or via synthesis, makes the Birch reduction an important tool in organic synthesis. 

The substitution of pure benzene by an electrophile will result in the formation of a monosubstituted product, which is capable of undergoing further substitution reactions. When designing the strategy for the synthesis of an aromatic compound, there are two principal points that must be borne in mind, namely first, the reactivity of the monosubstituted product compared with that of the original benzene and second, the position on the aromatic ring where the second substitution reaction will take place. These two issues will now be examined, and it will be seen that they are, at least to some extent, dependent upon each other. 

The Catellani s alkylation-alkenylation sequence using norbomene offers a useful synthetic method for 2,6-dialkylated 1-substituted benzenes. Lautens applied the reaction to the synthesis of fused aromatic compounds using ort/jo-substituted iodobenzenes and bromoalkenes. Reaction of o-iodotoluene (11) with ethyl 6-bromo-2-hexenoate (13) afforded the benzocarbocycle 14 via monoalkylation and intramolecular Heck reaction. It is important to use tri-2-furylphosphine (1-3) as a ligand [4]. Similarly the 2,5-disubstituted 4-benzoxepine 17 was obtained in 72% yield by the reaetion of 1-iodonaphthalene (15) with the unsaturated bromo ester 16 [5]. 

Friedel-Crafts alkylation is one of the most frequently used and widely studied reactions in organic chemistry. Since the initial discovery by Charles Friedel and James Mason Crafts in 1877, a large number of applications have emerged for the construction of substituted aromatic compounds. Friedel-Crafts alkylation processes involve the replacement of C—H bond of an aromatic ring by an electrophilic partner in the presence of a Lewis acid or Bronsted acid catalyst. Particularly, catalytic asymmetric Friedel-Crafts alkylation is a very attractive, direct, and atom-economic approach for the synthesis of optically active aromatic compounds. However, it took more than 100 years from the discovery of this reaction until the first catalytic asymmetric Friedel-Crafts (AFC) alkylation of naphthol and ethyl pyruvate was realized by Erker in 1990. Nowadays, owing to continued efforts in developing... 

Diazonium salts (Sections 20.6A, 20.6B, 20.7, and 20.8) Salts synthesized from the reaction of primary amines with nitrous acid. Diazonium salts have the structure [R-N N]+ X. Diazonium salts of primary aliphatic amines are unstable and decompose rapidly those from primary aromatic amines decompose slowly when cold, and are useful in the synthesis of substituted aromatics and azo compounds. 

The sulfonation reaction is less exothermic than halogenation or nitration. Hence, it is reversible, and desulfonation occurs in dilute aqueous acid. The reversibility of sulfonation forms the basis of the synthesis of some aromatic compounds because the sulfonic acid group may block a position on an aromatic ring, preventing substitution at that point. The sulfonic acid group is removed at the... 

Although transition-metal-mediated substitution reactions of aromatic nucleus have been well described in a number of books, a book that focuses on the transition-metal-mediated constmction of aromatic rings has not appeared to date. A book explaining the use of transition-metal-mediated aromatic ring constmction reactions for the complex aromatic compounds targeted would, therefore be useful for both academic and industrial chemists. For these reasons, in this book we demonstrate comprehensively how to use transition-metal-mediated aromatic ring constmction reactions for the synthesis of complex aromatic compounds. 

The synthesis of polycyclic aromatic compounds from substituted propargylic alcohols is based on a cascade cyclization initiated by the action of thionyl chloride (in pyridine) proceeding, apparently, via a diradical generated from the intermediate chlorinated benzoenyne-allene [279, 280]. The synthesis of benzannulated enyne-allene has been successfully achieved using the Claisen rearrangement of propargylic alcohol acetates. This route was used for the direct synthesis of several... 

The Hiyama coupling offers a practical alternative when selectivity and/or availability of other reagents are problematic. Hiyama et al. coupled alkyltrifluorosilane 74 with 2-bromofuran 73 to give the corresponding cross-coupled product 75 in moderate yield in the presence of catalytic Pd(Ph3P)4 and 3 equivalents of TBAF [65]. In this case, more than one equivalent of fluoride ion was needed to form a pentacoordinated silicate. On the other hand, alkyltrifluorosilane 74 was prepared by hydrosilylation of the corresponding terminal olefin with trichlorosilane followed by fluorination with C11F2. This method provides a facile protocol for the synthesis of alkyl-substituted aromatic compounds. 

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