Hydroxy-, derivatives tautomerism

This can be achieved by an indirect method. The lithio derivative is first reacted with a borate ester. Sequential acid hydrolysis and oxidation yields the corresponding hydroxy derivative. This procedure is illustrated by the conversion of 2-lithiobenzo[6]thiophene to 2-hydroxybenzo[6]thiophene, which exists predominantly in the 2(3//)-one tautomeric form (200) <70JCS(C)1926). 

The tautomerism of 2-substituted 1,3-azoles (154 155) is summarized in Table 39. Whereas amino compounds occur Invariably as such, all the potential hydroxy derivatives exist in the 0x0 form, and in this series the sulfur compounds resemble their oxygen analogs. There is a close analogy between the tautomerism for all these derivatives with the corresponding 2-substltuted pyrldines. 

The tautomerism of hydroxyindoles (and mercaptoindoles) has been reviewed (79HC1). As was pointed out previously (76AHCS1, p. 243) 2-hydroxyindoles 120 exist as lactams 121 (indolin-2-ones). The same holds for the corresponding A-hydroxy derivatives (1-hydroxyoxindoles) 121 (R = OH) (86AP1084,86JOC1704 90SC2133 94MI4). 

Interposition of a methylene group between the phenyl ring and the heterocycle leads to the benzyldiami nopyrimidines, a class of compounds notable for their antibacterial activity. Condensation of hydrocinnamate 54 with ethyl formate leads to the hydroxymethylene derivative 55. In this case, too, the heterocyclic ring is formed by reaction with guanidine. This sequence probably involves initial addition-elimination to the forniyl carbon to form 56 cyclization in this case involves simple amide formation. Tautomerization then affords the hydroxy derivative 57. This is converted to tetroxoprim (58) by first... 

Likewise, amine functions on the azepine ring at an unsaturated carbon center behave as enamines and undergo hydrolysis under both acid and alkaline conditions to the benzazepinones.15,64 8084 However, hydrolysis of dimethyl l-acetyl-5-piperidino-l//-l-benz-azepine-3,4-dicarboxylate(18) yields not the benzazepinone but the tautomeric 5-hydroxy derivative 19.13 Presumably, the enol form is stabilized by intramolecular hydrogen bonding. 

Recently, the hydroxy derivatives of furan, thiophene, and selenophene have been studied with regard to their physical properties and reactions. These compounds are tautomeric and if the oxygen function is placed in the 2-position they exist as unsaturated lactones and undergo carbon-carbon rearrangement, whereas the 3-hydroxy derivatives form oxo-enol tautomeric systems. By NMR the structures of the different tautomeric forms have been determined as well as the position of the tautomeric equilibrium and the rate of isomerization. 

There are no known derivatives of 29 and 30, except for the corresponding hydroxy derivatives, which can be present in several tautomeric forms. Therefore 46, the hydroxy derivative of 29, is also a hydroxy derivative of 31, as well as the corresponding trioxo derivative. A similar argument can be made for 47, which formally can be considered to be a hydroxy derivative of both 28 and 30. Spectroscopic studies of similar compounds suggested that these compounds exist almost entirely in their trioxo tautomeric forms [72JCS(P 1)977 78LA283). 

The H/D isotopic exchange in the uridine system (from starred nitrogen) may be explained by the mechanism (equation 8) involving dimerization of the hydroxy heterocycle70. Dimerization of hydroxy derivatives of aza-containing heterocycles plays an important role in assembling molecules, and in their tautomeric equilibria. 

The amino groups are replaced with oxygen. Although here a biochemical reaction, the same can be achieved under acid-catalysed hydrolytic conditions, and resembles the nucleophilic substitution on pyrimidines (see Section 11.6.1). The first-formed hydroxy derivative would then tautomerize to the carbonyl structure. In the case of guanine, the product is xanthine, whereas adenine leads to hypoxanthine. The latter compound is also converted into xanthine by an oxidizing enzyme, xanthine oxidase. This enzyme also oxidizes xanthine at C-8, giving uric acid. 

In l,3,4-oxadiazolo[3,2-a]pyridinium salts (15) an 0/As exchange can be achieved with tris(tri-methylsilyl)arsine in boiling acetonitrile to yield l,2,4-diazaarsolo[l,5-a]pyridines (16) (R = Me, Pr, Bu, Ph) (Equation (4)) <87TLl5li>. In a corresponding way the compound (17) with R = O-TMS is obtained. Methanolysis gives the hydroxy derivative (18) which exists exclusively in this tautomeric form and which can be O-acylated via the sodium salt (Scheme 3) <88TL3387>. 

OH hydroxy or tautomeric oxo form. b Mucochloric acid (decarboxylation). c R-7 = pyridyl, thienyl. d Meldrum s acid derivative. 

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. 

As discussed in Section 2.4.5.2, hydroxy derivatives of azoles fe.g. 622, 624, 626) are tautomeric with either or both of (i) aromatic carbonyl forms (e.g. 623, 627) (as in pyridones), and (ii) alternative non-aromatic carbonyl forms (e.g. 625, 628). In the hydroxy enolic form (e.g. 622, 624, 626) the reactivity of these compounds toward electrophilic reagents is greater than that of the parent heterocycles these are analogues of phenol. 

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. 

Hydroxy derivatives are expected to show the same tautomeric preferences for the oxo form in ortho and para positions to the nitrogen as in the parent monocycle. Thus, for the 2-hydroxythiazole (395) comparison of the spectroscopic data with the data for its AT-methyl and O-methyl derivatives is consistent with the oxo form the same preference has been shown for its [5,4-c] isomer (68CJC691). 

Thiono-mercapto and amino-imino tautomerism of azines. In the same heterocyclic systems, the stability of thiols with respect to the corresponding thione form is considerably higher than hydroxy derivatives with respect to their oxo forms. In the gas phase 2- and 4-mercaptopyridine are the major tautomers, e.g., 191. 15N NMR spectroscopy is useful for estimating the tautomeric composition of mercaptopyridines in solution. 2-Mercaptopyr-idine in acetone or methanol and 4-mercaptopyridine 191 in methanol or acetone/DMSO were estimated to be ca. 95% in the thione form, e.g., 192. This solvent effect can be attributed to the polarity of the thione tautomers <2006AHC(91)1>. 

A/-Hydroxy derivatives. Although A-hydroxypyrroles can in principle exist in three tautomeric forms, e.g., 234, 235, and 236, only the A-hydroxy form 234 is observed for l-hydroxy-2-cyanopyrrole <1973JOC173>. In the case of A-hydroxyindoles, where the potential loss of aromatic resonance energy is much less, both tautomers 237 and 238 coexist in solution with the relative proportions being dependent on the solvent <1967BSF1296>. 

Unlike the hydroxy derivatives, no tautomerism tends to exist in the simple 2- and 3-thiophenethiols <1977ACB198>, nor in benzo[. ]thiophene-3-thiol <1970JC2431>. 

---