Other Electrophilic Substitutions

Like pyridine, the azines are not normally attacked by diazonium cations, but since coupling reactions seldom involve extensive protonation of the substrate, the reactions become viable provided that sufficient numbers of activating groups are present, and if reactive diazonium salts are used. Pyridazin-3,4(l//,2//)-diones are among the few pyridazines 

The few examples of diazo coupling reported for pyrazines may not all be annular coupling (28G679 30G298 52JCS4870). 

Nitration of isatin, 7-methylisatin, 4,7-dimethylisatin, and 1-ethylisatin leads to the introduction of the nitro group into the 5-position. Nitration of 5-methylisatin gave 5-methyl-7-nitroisatin. Reaction of isatin and haloisatins with chlorosulfonic acid gave 5-chlorosulfonylisatins which were then converted into sulfonamides. 

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Ten years ago we became interested in the possibility of using nitration as a process with which to study the reactivity of hetero-aromatic compounds towards electrophilic substitution. The choice of nitration was determined by the consideration that its mechanism was probably better imderstood than that of any other electrophilic substitution. Others also were pursuing the same objective, and a considerable amount of information has now been compiled. 

Because of the limited range of aromatic compounds that react with diazonium ions, selectivity data comparable to those discussed for other electrophilic substitutions are not available. Because diazotization involves a weak electrophile, it would be expected to reveal high substrate and position selectivity. 

Other electrophilic substitutions proceed with difficulty, or not at all. Nitrosation and diazo coupling require the presence of the strongly activating dimethylamino group (see Section VIII). Bromine adds, in the presence of sunlight, to give tetrabromotetrahydrobenzofuroxan (48) the initial attack is probably free-radical in nature. The product can be dehydrobrominated to form 4,7-, or a mixture of 4,5- and 4,6-dibromobenzofuroxan, depending upon the conditions. More conventional electrophilic bromination conditions have been tried in an attempt to obtain a monosubstituted product, but without success. 

As with other electrophilic substitution reactions, there is practically no work available on the halogenation of isoxazoles with functional substituents. The only instance that indicates that the general pattern holds true here is the extremely rapid bromination of 3-anilino-5-phenylisoxazole (65), in which the isoxazole ring is the first to react with 1 mole of bromine, yielding... 

Arrhenius parameters for nitration of 4-aikylphenyltrimethyiammonium ions in nitric acid-sulphuric acid mixtures (Table 12). It was argued that the observed Baker-Nathan order of alkyl substituent effect was, in fact, the result of a steric effect superimposed upon an inductive order. However, a number of assumptions were involved in this deduction, and these render the conclusion less reliable than one would like it would be useful to have the thermodynamic parameters for nitration of the methyl substituted compound in particular, in order to compare with the data for the /-butyl compound, though experimental difficulties may preclude this. It would not be surprising if a true Baker-Nathan order were observed because it is observed for all other electrophilic substitutions in this medium1. 

The wide variation in the entropy factors for both the substituted phenyl and heterocyclic compounds and in particular for the methoxyphenyl and furan derivatives was considered to be strong evidence for solvent effects being predominant in determining the activation entropy. Consequently, discussion of the substituent effects in terms of electronic factors alone requires caution in this reaction. Caution is also needed since rates for the substituted phenyl compounds were only determined over a 20 °C range. The significance of entropy factors has also been indicated by the poor correlation of the data of the electrophilic reactivities of the heterocyclic compounds, as derived from protodemercuration, with the data for other electrophilic substitutions and related reactions572. 

Much less work has been done on electrophilic aliphatic substitution mechanisms than on nucleophilic substitutions, and the exact mechanisms of many of the reactions in this chapter are in doubt. For many of them, not enough work has been done to permit us to decide which of the mechanisms described in this chapter is operating, if indeed any is. There may be other electrophilic substitution mechanisms, and some of the reactions in this chapter may not even be electrophilic substitutions at all. 

For other electrophilic substitutions of the type RM — RC, see 10-93-10-117, which are discussed under nucleophilic substitutions in Chapter 10. See also 16-67. 

Other electrophilic substitution reactions on aromatic and heteroaromatic systems are summarized in Scheme 6.143. Friedel-Crafts alkylation of N,N-dimethyl-aniline with squaric acid dichloride was accomplished by heating the two components in dichloromethane at 120 °C in the absence of a Lewis acid catalyst to provide a 23% yield of the 2-aryl-l-chlorocydobut-l-ene-3,4-dione product (Scheme 6.143 a) [281]. Hydrolysis of the monochloride provided a 2-aryl-l-hydroxycyclobut-l-ene-3,4-dione, an inhibitor of protein tyrosine phosphatases [281], Formylation of 4-chloro-3-nitrophenol with hexamethylenetetramine and trifluoroacetic acid (TFA) at 115 °C for 5 h furnished the corresponding benzaldehyde in 43% yield, which was further manipulated into a benzofuran derivative (Scheme 6.143b) [282]. 4-Chloro-5-bromo-pyrazolopyrimidine is an important intermediate in the synthesis of pyrazolopyrimi-dine derivatives showing activity against multiple kinase subfamilies (see also Scheme 6.20) and can be rapidly prepared from 4-chloropyrazolopyrimidine and N-bromosuccinimide (NBS) by microwave irradiation in acetonitrile (Scheme... 

A few other electrophilic substitution reactions of the ring systems in this chapter are shown in Scheme 26 also. 

Wang et al. investigated the catalytic behavior of cation exchange resin supported lanthanide(III) salts of the general structure (31) (Scheme 4.15), prepared from Dowex, Amberlite, Amberlyst and other resins [99]. It turned out that Am-berlyst XN-1010 and Amberlyst 15 complexed best with lanthanides(III). Thus, among others, electrophilic substitution of indole with hexanal and Mukayiama-type aldol reaction of benzaldehyde with ketene silyl acetal proceeded in excellent yields under catalytic conditions (Scheme 4.16). 

The 2-position of dibenzofuran represents an average of 88% of the total reactivity of dibenzofuran for protodetritiation, protodetrimethylsilylation, and benzoylation, which accords well with the results recorded for other electrophilic substitution reactions of dibenzofuran. Mercuration and lithia-... 

This type of X -phosphorin reaction opens up new possiblities of preparing 4-substituted X -phosphorins by other electrophilic substitutions. They are now being studied by us. 

Nitration of dibenzofuran at C-3 as opposed to other electrophilic substitutions such as acetylation at C-2 has been attributed to the intervention of a charge-transfer process [21]. The C-N bond formation step is mechanistically closer to the nucleophilic process, the aromatic moiety being the electron-deficient species. It is understandable that N02. attacks at a nuclear carbon which is meta to the oxygen donor. 

Nitro-substituted pyrroles have usually been prepared by electrophilic substitution on preconstructed pyrrole rings. Like other electrophilic substitutions, nitration gives primarily... 

As in other electrophilic substitutions, mercuration of thienothiophenes (7) and (3) leads to a-substituted derivatives (102) and (103). When the a-positions are blocked as in (73), /3-mercuration occurs leading to the formation of the mercury derivative (104). In the early investigations on the classical thienothiophenes, organomercury derivatives were used for characterization purposes. Although the mercury function in (102)-(104) can be replaced by other electrophiles, at the present time the procedure has no practical significance <76AHC(19)123). 

It is possible to replace the ring hydrogens of many aromatic compounds by exchange with strong acids. When an isotopically labeled acid such as D2S04 is used, this reaction is an easy way to introduce deuterium. The mechanism is analogous to other electrophilic substitutions ... 

Like other electrophilic substitutions, nitration of a substituted benzene, where the substituent is electron withdrawing (N02, C02H, CN, and so on Table 22-6), generally produces the 1,3-isomer. To prepare the 1,4-isomer, less direct routes are necessary— the usual strategem being to use benzene derivatives with substituent groups that produce the desired orientation on... 

Now that we have determined that the intermediate in electrophilic aromatic substitution is usually a a complex (see, however, p. 394), let us return to a consideration of Reaction 7.76. Two factors probably combine to cause the observed isotope effect and base catalysis. First, the strong electron-donating groups stabilize the intermediate 76 (Equation 7.77) and make departure of the proton more difficult than proton loss in many other electrophilic substitutions. [Remember, however, that k1 < k2 (see p. 386).] Second, steric interactions between the large diazonium group and the nearby substituents increase the rate... 

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