Thiophenes 2-hydroxy-, tautomerism

The effect of substituents on the reactivity of heterocyclic nuclei is broadly similar to that on benzene. Thus mem-directing groups such as methoxycarbonyl and nitro are deactivating. The effects of strongly activating groups such as amino and hydroxy are difficult to assess since simple amino compounds are unstable and hydroxy compounds exist in an alternative tautomeric form. Comparison of the rates of formylation and trifiuoroacetylation of the parent heterocycle and its 2-methyl derivative indicate the following order of sensitivity to substituent effects furan > tellurophene > selenophene = thiophene... 

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. 

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 4- and 5-hydroxy-imidazoles, -oxazoles and -thiazoles (499, 501) and 4-hydroxy-pyrazoles, -isoxazoles and -isothiazoles (503) cannot tautomerize to an aromatic carbonyl form. However, tautomerism similar to that which occurs in hydroxy-furans, -thiophenes and -pyrroles is possible (499 500 503 504 501 502), as well as a zwitterionic... 

Benzo[6]thiophene, 2-acetyl-3-hydroxy-synthesis, 4, 892 Benzo[6]thiophene, 2-acyl-synthesis, 4, 918 Benzo[6]thiophene, 3-acyl-synthesis, 4, 918- 19 Benzo[6]thiophene, acylamino-synthesis, 4, 815 Benzo[6]thiophene, alkenyl-synthesis, 4, 917 Benzo[6]thiophene, 2-alkoxy-synthesis, 4, 929 Benzo[6]thiophene, 3-alkoxy-synthesis, 4, 929 Benzo[6]thiophene, 4-alkoxy-synthesis, 4, 930 Benzo[6]thiophene, 2-alkyl-synthesis, 4, 877-878 Benzo[6]thiophene, 2-alkylthio-synthesis, 4, 931 Benzo[6]thiophene, 2-amino-diazotization, 4, 810 reactivity, 4, 797 stability, 4, 810 synthesis, 4, 869, 924-925 tautomerism, 4, 38 Benzo[6]thiophene, 3-amino-cycloaddition reactions, 4, 68 synthesis, 4, 109, 881, 925 Benzo[6]thiophene, 4-amino-synthesis, 4, 925 Benzo[6]thiophene, 5-amino-synthesis, 4, 925 Benzo[6]thiophene, 7-amino-synthesis, 4, 925 Benzo[6]thiophene, 3-t-amyl-synthesis, 4, 915 Benzo[6]thiophene, 2-aryl-synthesis, 4, 881... 

The mechanism of the Fiesselmann reaction between methylthioglycolate and a,P-acetylenic esters proceeds via consecutive base-catalyzed 1,4-conjugate addition reactions to form thioacetal Enolate formation, as a result of treatment with a stronger base, causes a Dieckmann condensation to occur providing ketone 8. Elimination of methylthioglycolate and tautomerization driven by aromaticity provides the 3-hydroxy thiophene dicarboxylate 9. 

This 1,3-migration of hydrogen was also observed when 40 reacted with Lawesson s reagent to produce the dithiolactone 41. However, when y-hydroxy-a,P-unsaturated aldehyde 42 was reacted under similar conditions, thiophene 43 was prepared efficiently. These results are not surprising considering that the oxidation state of 42 is equivalent to the traditional saturated 1,4-dicarbonyl substrates of the Paal thiophene reaction via tautomerization of the double bond, and aromaticity is reestablished in the fully conjugated 43. 

The UV spectrum of 5-phenyl-3 hydroxythiophene is very similar to that of its methyl ether in alcoholic solution, indicating that it exists largely in the enol form in this solvent. The same coincidence of the wavelength maxima was also obtained for 5-phenyl-2-hydroxy-thiophene and its methyl ether. In chloroform solution, the maxima were shifted toward longer wavelengths, suggesting that the tautomeric equilibrium in this solvent is displaced more toward the keto form. ... 

Heterocyclic compounds carrying hydroxyl groups may be compared with phenols. Thomson has reviewed the tautomeric behavior of phenols often both tautomeric forms of polycyclic compounds such as naphthols can be isolated. Early work on hydroxy-thiophenes and -furans was also reviewed by Thomsond but until recently their chemistry has been in a somewhat confused state. A pattern is now beginning to emerge, at least for the a-substituted compounds, which appear to exist as A -oxo derivatives and to attain equilibrium slowly with the corresponding A -oxo forms. For the a-hydroxy compounds, the equilibrium generally favors the A -oxo form. 

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. 

This gives tautomeric mixtures119 when the tert-butyl group is removed. The methyl ether has been used to obtain 3-hydroxy-2-carbonyl derivatives in the selenophene series.120 The unsubstituted 2-hydroxyselenophene system has been prepared by hydrogen peroxide oxidation of 2-selenophene-boronic acid.121 However, in the 5-methyl-substituted system deboronation became such an important side reaction that 5-methyl-2-hydroxyselenophene had to be prepared by acid-catalyzed dealkylation of 5-methyl-2-fert-butoxy-selenophene. Both 2-hydroxy- and 5-methyl-2-hydroxyselenophene exist mainly as 3-selenolene-2-ones (93) and for the 5-methyl derivative it was possible to isolate the / ,y-unsaturated form (92) and follow the tautomeric isomerization. The activation parameters thus obtained were compared with those for the corresponding furan and thiophene systems. 

Equilibrium and rate constants for the keto-enol tautomerization of 3-hydroxy-indoles and -pyrroles are collected in Table 32 (86TL3275). The pyrroles ketonize substantially (103-104 times) faster than their sulfur or oxygen analogues, and faster still than the benzo-fused systems, indole, benzofuran, and benzothiophene. The rate of ketonization of the hydroxy-thiophenes and -benzothiophenes in acetonitrile-water (9 1) is as follows 2-hydroxybenzo[b]thiophene > 2,5-dihydroxythiophene > 2-hydroxythiophene > 3-hydroxybenzo[/ Jthiophene > 3-hydroxythiophene. 3-Hydroxythiophene does not ketonize readily in the above solvent system, but in 1 1 acetonitrile-water, it ketonizes 6.5 times slower than 2-hydroxythiophene (87PAC1577). 

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. 

Thioindoxyl 2-substituted synthesis, 4, 892 synthesis, 4, 880, 894, 927 tautomerism, 4, 728 Benzo[6]thiophene, 4-hydroxy-synthesis, 4, 905, 928 Benzo[i>]thiophene, 5-hydroxy-synthesis, 4, 928 Benzo[i>]thiophene, 6-hydroxy-synthesis, 4, 928 Benzo[6]thiophene, 7-hydroxy-synthesis, 4, 928 Benzo[f>]thiophene, 2-iodo-synthesis, 4, 934 Benzo[f>]thiophene, 3-iodo-synthesis, 4, 934 Benzo[6]thiophene, 2-mercapto-synthesis, 4, 931 tautomerism, 4, 38 Benzo[6]thiophene, 3-mercapto-synthesis, 4, 931... 

Thiophene, 2-hydroxy-5-methyl-synthesis, 4, 926 Thiophene, iodo-Grignard reagents, 4, 79, 831 photolysis, 4, 832 reactions, 4, 932 with phenyllithium, 4, 831 synthesis, 4, 835, 934 Ullmann coupling reactions, 4, 837 Thiophene, 2-isopropyl-3-methyl-synthesis, 4, 901 Thiophene, mercapto-reactions, 4, 78 stability, 4, 825 synthesis, 4, 80, 835, 930-931 tautomerism, 4, 38, 727 Thiophene, 2-mercapto-5-methylthio-synthesis, 4, 872 Thiophene, 2-methoxy-chloromethylation, 4, 759 Thiophene, 3-methoxy-chloromethylation, 4, 759 Thiophene, 5-methoxy-2,4-dinitro-Meisenheimer complexes, 4, 815 Thiophene, 2-methoxy-5-methyl-Vilsmeier formylation, 4, 759-760 Thiophene, 2-methoxy-3-nitro-reactions, 4, 827 Thiophene, 2-methyl-bromination, 4, 799-800 conformation, 4, 32 HNMR, 4, 730 metallation, 4, 773 synthesis, 4, 885, 887 trifluoroacetylation, 4, 751 Thiophene, 3-methyl-bromination, 4, 799-800 conformation, 4, 32 H NMR, 4, 730 metallation, 4, 60 oxidation, 4, 800... 

In the benzo[A] and benzol/] heterocycles 220 and 221, where the loss of ring resonance energy on tautomerism is much less than in the nonannulated heterocycles 217, the oxo tautomers 222 and 223 are energetically preferred. 2-Hydroxyindole 220 (X = NH) exists exclusively as the oxo tautomer 222 (X = NH) (oxindole). The hydroxy form of 2-hydroxybenzo[A]thiophene 220 (X = S) is detectable by NMR spectroscopy when its trimethylsilyl ether precursor is... 

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