Electrophilic attack at the 3-position

Pyridinones and quinolinones undergo electrophilic attack at the (3 -position (12,13) fairly easily and disubstitution is well known in the pyridine series. Pyridinones are more easily halogenated than benzene, but the highly acidic conditions used for nitration and sulfonation makes these less easy reactions. Electrophiles also attack at the oxygen (14), but this is considered as a substituent reaction and therefore will be dealt with in Chapter 2.06. 

The synthesis of the heteroarylcarboxylic acid chlorides is fraught with difficulties. When isolated, the acid chlorides are generally unstable and readily produce bisheteroaryl ketones (see Section 3.05.1.2.9). Using standard preparative procedures the increase in the acidity of the reaction medium can cause polymerization, whilst the addition of a base can result in the formation of compounds of the type (403) and (404). Attempts to prepare indole-2 -carboxylic acid chloride using thionyl chloride result in the isolation of sulfur-containing derivatives, which arise from electrophilic attack at the 3-position (64JOC178). 

Methylindole with DMAD in acetonitrile, which had been redistilled from phosphorus pentoxide, gave173,174 the azepine 261 which is formed by electrophilic attack at the 3-position of the indole to give 258, cyclization to 259 and opening of the four-membered ring as is well... 

Electrophilic attack on pyridine at the 2-position gives an unstable intermediate, with one of the resonance structures showing a positive charge and only six electrons on nitrogen. In contrast, electrophilic attack at the 3-position gives a more stable intermediate with the positive charge spread over three carbon atoms and not on nitrogen. 

The observation that carbenoids are capable of electrophilic attack at the 3-position of A -BOC-pyrrole may shed light on other carbenoid reactions that have stood out as rather unusual transformations. For example, a very useful [3- -2]-annulation between diazodimedone 1071 and ethyl 177-pyrrole-l-carboxylate leading to the tricyclic product 1072 was discovered (Scheme 208) <1995JOC2112>. It was proposed that the reactions occurred through initial cyclopropanation followed by ring opening of the pyrrolocyclopropane 1073 to a zwitterionic intermediate 1074. 

The (experimentally observed) preferential C-3-orientation of SjAr processes at pyridine can be considered with respect to the a-complexes involved. Comparison of the a-complexes resulting from the addition of electrophiles to the 2-, 3-, and 4-positions in pyridine shows that only electrophilic attack at the 3-position avoids participation of energy-rich nitrenium forms, which destabilize 0-complexes 9/11 relative to 10 ... 

Aromatic character in isoxazoles has been studied from a number of viewpoints, and these studies indicate that although isoxazole may be formally considered an aromatic system, the disposition of the ring heteroatoms modifies this character to an appreciable extent. From a qualitative viewpoint, thermal stability and electrophilic attack at the 4-position may be considered consistent with an aromatic character. Furthermore, NMR chemical shifts of the ring protons are consistent with those of an aromatic compound. References related to these studies may be found in Section 4.16.2.3.4. 

The ease with which furans react with electrophiles is forcibly demonstrated by the reaction (in CHC13 at 25°C) of 2,4-dimethylfuran with trichloroacetyl isocyanate to give the amide 56a.129 Attack at the 3-position is not easy, but still the azide of 3-(2-furyl)propenoic acid at 230°C gives an isocyanate that... 

Generally, electrophilic attack at the 3(4)-position is negligible unless both 2(5)-positions are filled or unless it is otherwise forced, as in a cyclization.140 Probably very small amounts of 3(4)-substitution occur and are overlooked in ordinary work though they can be found, if sought carefully, even in nitrations.141 Ciranni and Clementi142 discuss this matter (the aratio) in... 

The methyl groups on the pyridine ring result in a major difference in the reactivity of lutidines. In 3,5-lutidine the methyl groups act as electron donors tending to increase the stability of the tt-bonds, and activating the ring for electrophilic attack at the a-positions. The MOs in 3,5-lutidine show the it-levels pushed to lower energy... 

In the case of mercuration (soft electrophile), attack at the 2-position is favoured. These observations accord with predictions based on molecular orbital calculations, that hard electrophiles (nitronium ions) should attack at C-4 and soft electrophiles (e.g. HgS04) at C-2 (68JA223). Furthermore, very hard electrophiles (e.g. S03) are predicted to attack at C-3. This is hard to verify because pyridine 1-oxide reacts at C-3 as its conjugate acid (or... 

While the acetylation of phenylferrocene also produces three similar acetyl-phenylferrocenes (III, IV, V R = CGH5) (as well as a very small amount of an isomer in which the phenyl group is acetylated), the site reactivities are different (108, 109). The ring bearing the phenyl substituent is deactivated compared to the unsubstituted ring. In contrast to alkylferrocenes, the 2-position is favored over the 3-position. It has been postulated that this is the result of enhanced resonance stabilization of the transition state in substitution involving electrophilic attack at the 2-position. 

The 7r-electron excessive character of pyrrole and indole renders both systems extremely susceptible to electrophilic attack and the fused benzene rings of carbazole also undergo electrophilic substitution more readily than does an unsubstituted benzene ring. In contrast, the 2/7-isoindole system only survives intact during electrophilic substitution reactions under the mildest of conditions and the system is more susceptible to [ 4 + 2] cycloaddition reactions than is pyrrole. 1,1-Disubstituted IH-isoindoles generally undergo nucleophilic addition-elimination reactions across the 2,3-bond or yield products derived from an initial electrophilic attack at the 2-position. 

Although there appear to be no examples of the specific acid-catalyzed rearrangement of 3-substituted indoles to give the 2-substituted indoles, electrophilic substitution of 3-substituted indoles is known to proceed via the attack at the 3-position to give the... 

The position 3 is so much preferred in electrophilic substitution, that it is the site for primary attack even when it is already substituted. Jackson and co-workers255 have provided a considerable body of evidence that electrophilic substitution at the 2-position of 3-substituted indoles is an indirect process involving prior attack at the 3-position to give an indolenine derivative (30), which subsequently rearranges to a 2,3-disubstituted indole. 

In yet another investigation, these workers determined that 585-CN is susceptible to electrophilic attack at the 5-position, nucleophilic attack at the 1- (or 3-) position, dienophile attack at the 4,5-position, and Diels-Alder cycloaddition at its electron-deficient ring.437) The differences in regioselectivity are impressive. 

In the first case, the incoming electrophile will attack at the 4 position, because this is ortho to one alkyl group and para to the other. In the second case, the incoming electrophile will attack at the 3 position, because this is meta to the carboxyl group and ortho to the chloro group. (Strictly, in the last example, the favoured position of attack should be called the 2 position. This arises because the chlorine substituent has a higher priority than the carboxylic acid substituent when it comes to systematic naming. However, for the purposes of the above illustration, that refinement merely adds an unnecessary level of complexity.)... 

In equation 8.67, attack of the electrophile occurs at the (3 position to give a car-bene complex as the intermediate subsequent loss of CH3I produces the acyl-Re complex as the final product.94... 

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