177-Pyrrole, tautomerism derivatives

In many cases, substituents linked to a pyrrole, furan or thiophene ring show similar reactivity to those linked to a benzenoid nucleus. This generalization is not true for amino or hydroxyl groups. Hydroxy compounds exist largely, or entirely, in an alternative nonaromatic tautomeric form. Derivatives of this type show little resemblance in their reactions to anilines or phenols. Thienyl- and especially pyrryl- and furyl-methyl halides show enhanced reactivity compared with benzyl halides because the halogen is made more labile by electron release of the type shown below. Hydroxymethyl and aminomethyl groups on heteroaromatic nuclei are activated to nucleophilic attack by a similar effect. 

The methods outlined, of course, are readily applicable to a wide variety of substituted heterocycles like the carboxyl, hydroxy and mercapto derivatives of pyridines, pyridine 1-oxides, pyrroles, etc. The application to amines and to diaza compounds such as pyrimidine, where the two centers are basic, is obvious except that now 23 takes the role of the neutral compound, 21 and 22 the roles of the tautomeric first conjugate bases, and 20 the role of the second conjugate base. Extensions to molecules with more than two acidic or basic centers, such as aminonicotinic acid, pyrimidinecarboxylic acids, etc., are obvious although they tend to become algebraically cumbersome, involving (for three centers) three measurable Kg s, four Ay s, and fifteen ideal dissociation constants (A ), a total of twenty-two constants of which seven are independent. 

The solid-state interaction of enamines (428, 333a) with trans-l,2-diben-zoylethene (87) provides quantitative yields of the pyrrole derivatives 445 or 446 [140]. These remarkable 5-cascades consist of initial vinylogous Michael addition, enol/keto tautomerism, imine/enamine tautomerism, cyclization, and elimination, all within the crystal without melting. A waste-free extraordinary atom economy is achieved that cannot nearly be obtained in solution. The milling times are unusually long here (3 h) but it s certainly worth the effort... 

Chemical shifts for aromatic azoles are recorded in Tables 17-20. Fast tautomerism renders two of the C-13 chemical shifts equivalent for the NH derivatives just as in the proton spectra (Table 17). However, data for the A-methyl derivatives (Table 18) clearly indicate that the carbon adjacent to a pyridine-like nitrogen shows a chemical shift at lower field than that adjacent to a pyrrole-like N-methyl group (in contrast to the H chemical shift behavior). In azoles containing oxygen (Table 19) and sulfur (Table 20), the chemical shifts are generally at lower field than those for the wholly nitrogenous analogues, but the precise positions vary. 

Hydroxy derivatives of thiophene, pyrrole and furan (240 and 243) are tautomeric with alternative non-aromatic carbonyl forms (241, 242 and 244), as discussed in Section 2.3.5.2. 

Upon reaction with nitrous acid, indole produces a complex mixture of products. In addition to 3-oximino-3H -indole (16), which is the stable tautomeric form of 3-nitrosoindole (17), dimeric products of the type (18) and (19) are also formed. In contrast, (16) appears to be the sole product of the nitrosation of indole with amyl nitrite and sodium ethoxide (72HC(25-2)537). Studies of the nitrosation of pyrrole are somewhat indecisive. The mononitrosopyrrole, obtained from the reaction of pyrrole with nitrous acid, has not been fully characterized, but there is some evidence that nitrosation of pyrrole with amyl nitrite and sodium ethoxide leads to the sodium salt of the 3-nitroso derivative. However, upon the addition of acid, the product rearranges to give the oxime of 3-formylisoxazole (20) (B-77MI30502). 

The p-Ka values for the NH acid dissociation of pyrrole and its benzo derivatives are closely similar. Recent measurements conducted in DMSO set the values at 19.90, 20.95 and 23.05 for carbazole, indole and pyrrole, respectively (81JOC632), although pKa values as low as 17.5 for pyrrole and 16.97 for indole have been recorded (67T2855). No reliable values are available for the NH dissociation of isoindole, as such measurements are complicated by the tautomeric equilibrium between the 1H and 2H isomers. It is apparent that many of the reactions conducted under strongly alkaline conditions and described in other sections could well proceed on the heterocyclic anions. In this section the discussion is centred upon reactions in which the C or N anionic species of the heterocycles are specifically produced. 

As with the alkyl and aryl derivatives of the pyrrolenines and indolenines, a tautomeric equilibrium has also been noted between the pentachloro-2//- and -3H- pyrroles, such that when the 2//-pyrrole, produced by chlorination of 2,3,4,5-tetrachloropyrrole or of 3,4-dichloromaleimide, is allowed to react with dienophiles, the adducts are those formed by cycloaddition with the 3H-pyrrole tautomer (Scheme 84) (80JOC435, 80JA7862, 81JOC3036). Cycloaddition with cyclopentadiene occurs on the 2H-pyrrole, which behaves as the dienophile. 

The C-2 and C-3 hydroxy derivatives of pyrrole are special in the sense that the tautomeric equilibria favor the pyrrolinone structures (see Section 3.04.6.2). Furthermore, the general synthetic methods are not usually applicable so that we will call attention in this section not only to the methods of directly introducing these substituents, which are rare, but also to those ring construction processes which specifically give the pyrrolinones and indolinones. The indole derivatives have widely used trivial names, oxindole (5) for indolin-2-one and indoxyl (6) for indolin-3-one, Carbocyclic hydroxy substituents in indole and carbazole, on the other hand, for the most part act as normal aromatic phenolic groups. These compounds are usually prepared by application of the standard ring syntheses. 

Azoloazoles represent interesting objects for study. Most of these structures are very unstable and can be regarded only as intermediates <1998JPR687>. Nonetheless, some, for instance pyrrolotetrazole and its derivatives, are relatively stable and can exist as the tautomeric forms 17 and 18 (Equation 2). In these structures only one of the heterocycles remains aromatic, for example, it is the tetrazole ring in the 5//-tautomer 18 and the pyrrole ring in the 1/7-tautomer 17. 

The substitution reaction may occur on a prototropic nonaromatic form. Both types of tautomerism, i.e., that prevailing in the parent heterocycles (pyrrole-pyrrolenine, indole-indolenine) and that typical of the hydroxy and amino derivatives, must be considered. 

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