2- -3-hydroxythiophenes enols

In the absence of oxygen, these thiolene-2-ones are rather stable and have been kept at 0°C for several months. 3-Hydroxythiophene, on the other hand, which has been prepared in low yield from 3-thio-phenemagnesium bromide in the same way as the 2-isomer, or through decarboxylation of 3-hydroxy-2-thiophenecarboxylic acid, "" is very unstable. Its IR spectrum indicates that it also exists as a tautomeric mixture largely in its enolic form. ... 

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. ... 

The hydroxythiophenes which exist predominantly as the thiolen-2-ones also show reactions characteristic of the enol form. They can be methylated at the oxygen with dimethyl sulfate of diazomethane and they can also be acylated. - - They also react as thio-lene-2-ones showing a reactive methylene group which can be condensed with benzaldehyde. The danger of using chemical reactivity data for drawing conclusion as to the physical state of these tautomerizable systems has been pointed out. ... 

Hydroxythiophenes 56 have two possible keto tautomers (57 and 58) [for review see (86HC1)]. As has been pointed out earlier (76AHCS1, p. 229), the tautomerism of 5-substituted eompounds was extensively studied by Lawesson and eoworkers (63T1867) and by Hornfeldt (63MI1 68MI1). For 5-alkyl eompounds, only the keto forms were present, whereas with R = phenyl, thienyl and ethoxyearbonyl substantial amounts of the enol forms were deteeted. Computations for the parent system (R = H) showed that the 4 -thiobutenolide of type 57 is most stable (Table VII). 

Snyder and his co-workers assigned structures 48 and 49 to these j6-hydroxythiophene derivatives on the basis of chemical evidence and infrared and nuclear magnetic resonance spectral data. Infrared and nuclear magnetic resonance spectra further indicate that compounds of type 49 exist as dimers, probably hydrogen bonded, when R = OC2H5 or CH3, but as monomeric enols when R = H. ... 

The ionization potentials, using mass spectrometry, for both 2-hydroxy-and 3-hydroxythiophenes have been compared with data for compounds derived from either tautomeric form in order to analyze the tautomeric composition.124 125 In the 2-hydroxy-substituted system the enol isomer could not be detected. Of the two possible unsaturated lactones the oc,/l-unsaturated form was the major isomer. In the 3-hydroxy-substituted case both the oxo form and the enol form are important. The position of the equilibrium was compared with those of the corresponding furan and sele-nophene systems for both isomers. 

Replacement of a benzene ring by its isostere, thiophene, is one of the more venerable practices in medicinal chemistry. Application of this stratagem to the NSAID piroxicam, gives tenoxicam, 136, a drug with substantially the same activity. The synthesis of this compound starts by a multi-step conversion of hydroxythiophene carboxylic ester 130, to the sulfonyl chloride 133. Reaction of that with N-methylglycine ethyl ester, gives the sulfonamide 134. Base-catalyzed Claisen type condensation serves to cyclize that intermediate to the p-keto ester 135 ( shown as the enol tautomer). The final product tenoxicam (136) is obtained by heating the ester with 2-aminopyridine [22],... 

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). 

B3LYP/6-31G calculations on the tautomers of succinic anhydride 105 show that the enols 106 and 107 are disfavored by 24.1 and 41.1 kcalmoF1, respectively. This is in spite of the aromatic stabilization in the furan 107 and in line with the general instability of anhydride enols . For 2-hydroxythiophene 110, similar calculations show the following relative stability 108 (0.0kcalmol-1), 109 (4.23 kcalmoF1), and 110 (15.72kcal mol J) . 

The 3-hydroxy form 233 is more favorable in thiophene systems, which enjoy greater aromaticity <2000J(P2) 1453>. Thus, 2-methyl-3-hydroxythiophene exists at equilibrium as a mixture of the oxo form 232 (R = Me, R2 = H) (20%) and the enol form 233 (R = Me, R2 = H) (80%) <1986HC(44/3)1>. For the / /7-butyl derivative... 

The enolic form, 2-hydroxythiophene 191 (Figure 46), has been generated from its ttimethylsilyl ether 192 in DMS0- 6 at 32°. This may be regarded as the enolic form of a thioester and it is converted in more than 99% into the keto forms 193 and 194 at equilibrium <2000AHC(76)105, 1968MI343, 1967JOC3028>. 

Spectral evidence for 3-hydroxythiophenes shows them to exist as mixtures of both forms 207 and 208 and the keto form 208 to predominate by a factor of 2.9 <1986TL3275, 1989JA5346>. It is, however, unstable and tends to dimerize to the bithienyl 209 <1990CC375>. 3-Hydroxythiophene was prepared from the trimethylsilyl derivative and was sufficiently stable for its NMR spectrum to be obtained in a variety of solvents <1989JA5346>. In most cases, 100% of the enol form was detected, but in CCI4 both tautomers were observed. 

Few hydroxythienopyridines have been described. A major point of interest is the extent to which the compounds exist as the hydroxy or keto tautomer. Derivatives in which the group is attached to the pyridine ring would be expected to resemble their quinoline or isoquinoline analogs, but, in view of the fact that hydroxythiophenes exist to some extent in keto forms, the genuinely phenolic properties of hydroxy groups on the benzene rings of the isosteric systems might not be reproduced in thienopyridines. 1-Hydroxyisoquinoline and 2- and 4-hydroxy-quinoline exist almost exclusively in the keto forms, whereas 3-hydroxyquinoline and 4-hydroxyisoquinoline are extensively enolized in 3-hydroxyisoquinoline the two forms are of comparable stability and which one predominates is dependent on the solvent. A similar pattern is... 

Compounds such as (246) having a carbonyl substituent at position 3 and a hydroxyl at 2 exist exclusively in the enol form. On the other hand, if the ester is located at position 5, then about 15% of the keto form is seen at equilibrium along with 85% of the enol. 3-Hydroxythiophene-4-carboxylic acid esters seem to exist as a mixture of both tautomers <86HC(44/3)l>. 

Compounds containing a reasonable proportion of an enolic hydroxyl group, i.e, C=(3—OH, usually give a deep color with ferric chloride, and this has often been used as a qualitative test. In this way, 2-hydroxythiophene has been shown to exist, at least in part, in the hydroxy form. ... 

The keto-enol tautomeric equilibrium of 3-hydroxythiophenes 50(OH) [thiophene-3(2H)-ones 50(=O)] was systematically studied [91]. H and NMR spectra were analyzed completely (e.g., 50(OH) 5(C-2) =98.0ppm, i5(C-3) = 155.1 ppm 50(=O) 5(C-2) = 36.6ppm, 5(C-3) = 203.4ppm) and the equilibria determined. The amount of keto tautomer is greatest in nonpolar solvents [91]. Using the same methodology, the tautomeric equihbrium of the thione-thiol forms of l,3-thiazolidine-2-thione was examined [92]. 

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