Aromatic and Heteroaromatic Substrates

The effects of a-CD on the bromination of other substrates have been studied recently (Javed, 1990 Tee et al., 1990a Tee and Javed, 1993), the object being to see if the catalytic effects observed earlier with phenols (Tee and Bennett, 1988a) are peculiar to these substrates or more general. Broadly speaking, various aromatic and heteroaromatic substrates (Table A4.4) showed behaviour (k /k2u = 1.7 to 10 XTS = 0.2 to 1.2 mM) very similar to that of phenols, and so the catalytic effect appears to be fairly general. The oxidation of formic acid by bromine also shows catalysis by a-CD (Han et al., 1989 Tee et al., 1990a). 

Electrochemical induction of the reaction (Pinson and Saveant, 1974), as shown to occur in a number of cases with aromatic and heteroaromatic substrates (Saveant, 1980a, 1986, 1988), also provides evidence for the Sr I mechanism. The electrochemical approach allows, in addition, a quantitative analysis of the mechanism and reactivity problems and will be described in this connection in the next subsection. 

More attention has been devoted to aromatic and heteroaromatic substrates since first reported in 1983 [40]. The results are shown in Table 2 [25, 41-51]. All these reactions were run with nickel complexes associated with a phosphane or bpy ligand. Depending on the experimental conditions, the polymers were either precipitated during the electrolysis or deposited as films at the surface of the electrode. The method is also convenient to prepare copolymers from a mixture of two aryl dihalides. A mechanistic investigation on the nickel-bpy catalyzed polymerisation has been reported very recently [52]. 

To demonstrate the catalytic efficiency of thiourea 9 and urea 16 (each 10mol% loading), Friedel-Crafts alkylation of various aromatic and heteroaromatic substrates was performed at room temperature in toluene as well as under solvent-free conditions. The results for the products 1-7 shown in Scheme 6.6 revealed that in all cases the 9-catalyzed reactions gave higher yields. In toluene N-methylpyrroIe reacted smoothly to give the 2-substituted Friedel-Crafts adduct 1, while the adducts 3-5 and 7 formed slowly and required longer reaction times (72 h). The... 

Reaction of Ar-fluoro reagents la and 2 with ort/ < -metalatcd aromatic and heteroaromatic substrates allows regiospecific access to a variety of fluorinated products, e.g. formation of 7.143... 

The hydrogen-isotope exchange reactions have already been discussed in previous sections. For various aromatic and heteroaromatic substrates, standard reaction rates in protodedeuteration and in nitration have been obtained. A plot of these shows a wide scatter. This means that there is no simple relation between these two measures for the susceptibility to electrophilic attack. No single reactivity index can be used as a measure to derive a unique order of the susceptibility of individual ring positions towards electrophilic attack (75TL1395). 

This chain process requires an initiation step. In a few systems a thermal (spontaneous) initiation is observed. One of the methods consists in the formation of the radical anion of the substrate by reaction with alkali metals in liquid ammonia. Electrochemical initiation is an approach that has been successful in a considerable number of cases with aromatic and heteroaromatic substrates [14]. Other possibilities include the use of Fe+2 [15-18], Sml2 [19], or Na(Hg) [20]. However, the most extensively used method is the photoinitiation, and it has proven extremely suitable for synthetic purposes Even though it is a widely used initiation method, there are not many mechanistic studies of this step. 

There are many examples of this type of reaction with both aromatic and heteroaromatic substrates. For successful electrocyclization, the central alkene must have Z geometry, however, as the action of light on stilbenes promotes E-Z isomerization, it is possible to start with either geometrical isomer of the substrate, or indeed a mixture of isomers. In a synthesis of cervinomycin A, photochemical electrocyclization of the mixture of E- and Z-diaryl alkenes 347 gave the polycyclic aromatic compound 348 after oxidation with iodine (3.219). ... 

In 2004, Ricci and coworkers reported a sustainable Friedel-Crafts adulation of nitroalkenes with various aromatic and heteroaromatic substrates utilising 10 mol% of thiourea 8 under solvent-free reaction conditions. When applied to indoles, this method provides excellent yields and high selectivities (Scheme 19.8). Additionally, allqrlation at the difficult 2-position of the 3-methylindole was accomplished in a solvent-free reaction with the assistance of microwave irradiation (MW). 

The transition-metal-catalyzed direct alkenylation reactions of aromatic and heteroaromatic substrates accompanied by C-H bond cleavage have been developed significantly in past few decades. These reactions provide powerful tools for preparing a wide range of -conjugated molecules from simple, readily available... 

Electrochemical initiation is an approach that has been snccessful in a considerable number of cases with aromatic and heteroaromatic substrates. The Saveant group has studied most of these reactions [11]. According to the difference of the standard potentials between the ArX/ArX " and ArNu/ArNu couples, two different situations may arise. If E (ArX/ArX ") > E (ArNu/ArNu ") and ArX fragments slowly, Ar" and ArNu " are formed far from the electrode surface. The ArNu " formed can be oxidized at the electrode surface or in the solntion (Eq. 10.2) to continue the propagation cycle. Under this situation, complete conversion of ArX into ArNu can be obtained with a... 

The direct insertion ofZn metal in the presence of LiCl can be quite conveniently performed in THF as solvent. A broad range of aromatic and heteroaromatic substrates undergoes this process, offering aromatic zinc halides, mostly in excellent yields and functional group compatibility. 

Several of these // -disubstituted [ C]formamides have demonstrated utility in C-[ " C]formylations of electron-rich aromatic and heteroaromatic substrates via the Vilsmeyer-Haack reaction °. In the presence of POCI3, Cl2(0)P0P(0)Cl2, (COCl)2 or (CF3S02)20 they can C-formylate benzene and naphthalene derivatives that possess an electron-releasing substituent (0-alkyl, S-alkyl, A -dialkyl) as well as anthracene, pyrrole. 

An important use of H CHO has been found in amino[ " C]methylations of nucleophiles in the presence of primary and secondary amines (Mannich reaction). Nucleophilic substrates include C—H acidic aliphatic compounds (e.g. aldehydes, ketones, esters, nitroalkanes and nitriles), and reactive aromatic and heteroaromatic substrates such as indoles, furans and phenols. The amino[ C]methylations of some C—H acidic methyl, methylene and methine substrates are exemplified in Figure 5.44. The immediate products, alkyl- or dialkylamino[ C]methylene derivatives ( Mannich bases ), can undergo a number of useful synthetic transformations. Condensation of H CHO with acetophenone and dimethylamine provided the carbon- 14-labeled /3-aminoketone 147 in 51 % yield. /3-Aminocarbonyl compounds such as 147. whQe stable at room temperature, can eliminate... 

For unactivated aromatic and heteroaromatic substrates, where a polar substitution is not favorable, nucleophilic substitution is feasible through processes that involve electron transfer (ET) steps. In these reactions, an aromatic compound bearing an adequate leaving group is substituted at the ipso position by a nucleophile in a unimolecular radical nucleophilic substitution mechanism (or S,y.jl), which is a chain process that involves radicals and radical anions as intermediates. 

Numerous examples exist in which TMEDA not only facilitates the lithiation of aromatic and heteroaromatic substrates but also controls the regioselectivity of lithiation. While tertiary ben-zamides are susceptible to nucleophilic attack by n-butyllithium to give aryl butyl ketones, the use of s-ButyllithiumnMEDA in THF at —78 °C provides the synthetically useful ortho metalated tertiary benzamide which may be treated with a large variety of electrophiles (eq 4). Even with compounds having a second more acidic site the above conditions allow ortho lithiation to take place under kinetic control. Thus a p-toluamide is ortho lithiated with s-butyllithium/TMEDA in THF at —78 °C, but when Lithium Diisopropylamide is used as the base in THF at 0 °C the thermodynamically favored benzyllithium species is obtained (eq 5). The very marked influence of TMEDA on the lithiation of naphthyl methyl ether in hydrocarbon solvents is dramatically illustrated in the example in eq 6. ... 

---