Aromatic substitution by metalation

Aromatic Substitution By Metal Catalysis or Other Complex Mechanisms 481... 

Phase transfer was used to catalyze nucleophilic aromatic substitutions by Makosza et al. in 1974.201 202 Zoltewicz203 has given a good early review of various methods and has compared other techniques that make use of polar solvents, transition metals, and monoelectron transfers. 

Enolase type activity is displayed in the efficient supramolecular catalysis of H/D exchange in malonate and pyruvate bound to macrocyclic polyamines [5.32]. Other processes that have been studied comprise for instance the catalysis of nucleophilic aromatic substitution by macrotricyclic quaternary ammonium receptors of type 21 [5.33], the asymmetric catalysis of Michael additions [5.34], the selective functionalization of doubly bound dicarboxylic acids [5.35] or the activation of reactions on substituted crown ethers by complexed metal ions [5.36]. 

As in chromatographic separation, the p Xylene contained/in an aromatic Cg cut must be retained preferentially on a solid and then recovered after displacement by an eluant. Type or T zeolites are preferably used to do this (0.9 0.2 Na2Q, AI2O3, w Si02 > H2O with 3 < w < 9 and y < 8) whose sodium ions have been substituted by metals, alone or in pairs, belonging to the alkali, earth alkali and rare earth groups etc, and especially by barium and potas um ions. The separation relies on the formation of association complexes in the presence of the substitution metals which, in pairs, display a certain synergy in their activity. 

The development of methods for aromatic substitution based on catalysis by transition metals, especially palladium, has led to several new methods for indole synthesis. One is based on an intramolecular Heck reaction in which an... 

Reduction of arenes by catalytic hydrogenation was described m Section 114 A dif ferent method using Group I metals as reducing agents which gives 1 4 cyclohexadiene derivatives will be presented m Section 1111 Electrophilic aromatic substitution is the most important reaction type exhibited by benzene and its derivatives and constitutes the entire subject matter of Chapter 12... 

The six-position may be functionalized by electrophilic aromatic substitution. Either bromination (Br2/CH2Cl2/-5°) acetylation (acetyl chloride, aluminum chloride, nitrobenzene) " or chloromethylation (chloromethyl methyl ether, stannic chloride, -60°) " affords the 6,6 -disubstituted product. It should also be noted that treatment of the acetyl derivative with KOBr in THF affords the carboxylic acid in 84% yield. The brominated crown may then be metallated (n-BuLi) and treated with an electrophile to form a chain-extender. To this end, Cram has utilized both ethylene oxide " and dichlorodimethyl-silane in the conversion of bis-binaphthyl crowns into polymer-bound resolving agents. The acetylation/oxidation sequence is illustrated in Eq. (3.54). 

The a-selectivity is illustrated by the fact that 2-alkyl-, > 2-methoxy-, > and 2-alkyIthio-thiophenes and alkyl thenyl sul-fides ° are metalated exclusively in the 5-position. In electrophilic aromatic substitution, as previously mentioned, an appreciable amount of 3-substitution is obtained with some of these groups. After acetalization ketones can also be metalated. Thus from the diethyl ketal of 2-acetylthiophene, 2-acetyl-5-thiophenealdehyde was obtained after metalation with n-butyllithium followed by the reaction of the metalorganic compound with A,A -dimethylformamide. ... 

The unfused cyclobutadiene system is stable in complexes with metals (see Chapter 3), but in these cases electron density is withdrawn from the ring by the metal and there is no aromatic quartet. In fact, these cyclobutadiene-metal complexes can be looked upon as systems containing an aromatic duet. The ring is square planar, the compounds undergo aromatic substitution, and NMR spectra of monosubstituted derivatives show that the C-2 and C-4 protons are equivalent. ... 

With the ArH ArTlX2 Arl reaction sequence available as a rapid and reliable probe for aromatic thallation, a detailed study was undertaken of the various factors affecting orientation in this electrophilic metallation process (153). The results, which are summarized below, demonstrate that aromatic thallation is subject to an almost unprecedented degree of orientation control coupled with the ease with which thallium can then be displaced by other substitutent groups (this aspect of the synthetic exploitation of aromatic thallation is discussed in detail below), the sequential processes of thallation followed by displacement represent a new and versatile method for aromatic substitution which both rivals and complements the classic Sandmeyer reaction. 

Figs. 11 and 12 show typical mo diagrams for square planar and octahedral complexes. Inspection reveals that the metal orbital (z is the axial direction) in a square planar complex is involved in the n bonding system and available for a bonding in the transition state. This is a feature shared by nucleophilic substitution at square planar complexes with the spectacularly associative nucleophilic aromatic substitutions. The octahedral complexes discussed in this chapter... 

Typically, the reaction mechanism proceeds as follows [6], By photoreaction, two chlorine radicals are formed. These radicals react with the alkyl aromatic to yield a corresponding benzyl radical. This radical, in turn, breaks off the chlorine moiety to yield a new chlorine radical and is substituted by the other chlorine, giving the final product. Too many chlorine radicals lead to recombination or undesired secondary reactions. Furthermore, metallic impurities in micro reactors can act as Lewis catalysts, promoting ring substitution. Friedel-Crafts catalyst such as FeClj may induce the formation of resin-Uke products. 

Synthetically important substitutions of aromatic compounds can also be done by nucleophilic reagents. There are several general mechanism for substitution by nucleophiles. Unlike nucleophilic substitution at saturated carbon, aromatic nucleophilic substitution does not occur by a single-step mechanism. The broad mechanistic classes that can be recognized include addition-elimination, elimination-addition, and metal-catalyzed processes. (See Section 9.5 of Part A to review these mechanisms.) We first discuss diazonium ions, which can react by several mechanisms. Depending on the substitution pattern, aryl halides can react by either addition-elimination or elimination-addition. Aryl halides and sulfonates also react with nucleophiles by metal-catalyzed mechanisms and these are discussed in Section 11.3. 

Aromatic nitro compounds undergo nucleophilic aromatic substitutions with various nucleophiles. In 1991 Terrier s book covered (1) SNAr reactions, mechanistic aspects (2) structure and reactivity of anionic o-complexes (3) synthetic aspects of intermolecular SNAr substitutions (4) intramolecular SNAr reactions (5) vicarious nucleophilic substitutions of hydrogen (VNS) (6) nucleophilic aromatic photo-substitutions and (7) radical nucleophilic aromatic substitutions. This chapter describes the recent development in synthetic application of SNAr and especially VNS. The environmentally friendly chemical processes are highly required in modem chemical industry. VNS reaction is an ideal process to introduce functional groups into aromatic rings because hydrogen can be substituted by nucleophiles without the need of metal catalysts. 

A specific case of the carbonium ion mechanism [Eq. (5)] with reasonable plausibility is decarboxylation of metal arenoates by classic electrophilic aromatic substitution [Eq. (12)]. This mechanism would be favored by electron-donating substituents and has been invoked to explain the relative ease of decarboxylation of p-methoxybenzoic acid in molten mercuric trifluoroacetate (77) as well as the very facile decarboxylation on reaction of polymethoxybenzoic acids with mercuric acetate (18) (see below). 

In more recent work by other researchers, sealed-vessel microwave technology has been utilized to access valuable medicinally relevant heterocyclic scaffolds or intermediates (Scheme 6.120) [240-245]. Additional examples not shown in Scheme 6.120 can be found in the most recent literature (see also Scheme 6.20) [246-249]. Examples of nucleophilic aromatic substitutions in the preparation of chiral ligands for transition metal-catalyzed transformations are displayed in Scheme 6.121 [106,108]. 

In most cases, construction of axial nonracemic biaryls can be realized by metal-mediated intramolecular biaryl coupling in which the chirality is induced by ort/io-substituted auxiliaries in an aromatic system. 

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