2- Hydroxythiophenes, tautomers

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). 

DFT Results for 2-Hydroxythiophene and the Corresponding Keto Tautomers" (99UP1)... 

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],... 

The tautomer (78) is the most stable form of 2-hydroxy thiophene (76). The conjugation available between the double bond stabilizes this form over (77). The position of equilibrium can, of course, be affected by other substituents on the thiophene ring. Likewise 3-hydroxythiophene (79) occurs chiefly as its tautomer (80). 

Anklam, E., Ghaffari-Tabrizi, R., Hombrecher, H., Lau, S., and Margaretha, P. (1984) Synthesis and photochemistry of 2,2-dimethyl-3(2H)-fhiophenone, a ketonic tautomer of 3-hydroxythiophene. Helvetica Chimica Acta, 67, 1402-1405. 

A number of important families of heterocycles belong to this class and many of the important systems are oxo derivatives. 2-Hydroxyfuran 64 exists almost exclusively as the equilibrating 3H- and 5//-furan-2-one tautomers 66 and 67. Tautomerism favoring the nonconjugated isomers also occurs in hydroxypyrroles and hydroxythiophenes. Similar behaviour is observed with simple amino derivatives 2-aminofuran 65 is too unstable to be detected <2006AHC (92)1 >. The 3-oxo tautomer 68 is the preferred form of 3-hydroxyfuran. 

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) . 

R BT, R2 = H) the equilibrium mixture is 232 (45%) and 233 (55%). 3-Hydroxythiophene 233 (R1 = R2 = H), prepared from the trimethylsilyl ether, is sufficiently stable for its 1H NMR spectrum to be obtained in a variety of solvents <1989JA5346>. In CC14 both tautomers are observed, contrary to an earlier report where only the oxo form was observed <1986TL5155>. Electron-withdrawing substituents, such as alkoxycarbonyl, generally cause the hydroxy form to predominate <1965T3331>. 

The relative rates of ketonization of hydroxythiophenes and hydroxybenzo[A]thiophenes in acetonitrile-water (9 1) are as follows 2-hydroxybenzo[A]thiophene > 2,5-dihydroxythiophene > 2-hydroxythiophene > 3-hydroxy-benzo[A]thiophene > 3-hydroxythiophene (Table 38). 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 <1987PAC1577>. The solvent has a significant effect on the equilibrium constants <1989JA5346>. In general, for the benzo b systems, increasing solvent polarity favors the hydroxy tautomer, which becomes the almost exclusive species in 2-acetyl <1965T3331> and 2-aryl <1976CS(9)216> derivatives, even in nonpolar media. 

Table 74 DFT results for 2-hydroxythiophene and the corresponding keto tautomers ...

Halo substituents do not influence the general tautomeric patterns of the hydroxythiophenes <2000J(P2)1453>. The trichlorinated hydroxythiophenes are stable when kept under nitrogen. The hydroxythiophenes with a bromine substituent, however, started to polymerize quite rapidly, even when kept at temperatures below 0 °C under nitrogen. The carbonyl structure of 2,5-dihydrothiophen-2-one 198bis the only detectable tautomer of compound 198. 

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. 

As in the case of 3-hydroxythiophenes, the benzo analogue is also unstable. There have been conflicting reports as to whether the hydroxy tautomer 213 or the keto form 214 is more stable. IR evidence indicates that in the solid state, it exists in the keto form <1958JCS1217>. 

These compounds are much more difficult to handle and much less accessible than phenols. Neither 2-hydroxythiophene nor its 4-thiolen-2-one tautomer are detectable, the compound existing as the conjugated enone isomer, 3-thiolen-2-one, which can be obtained directly by oxidation of thiophene. ... 

The presence of alkyl, or other groups, both stabilise the oxy compounds and the double bond to which they are attached. In these more stable compounds alternative tautomers are found, thus 5-methyl-2-hydroxythiophene exists as a mixture (actually separable by fractional distillation ) of the two enone tautomers and ethyl 5-hydroxythiophene-2-carboxylate is in the hydroxy-form to the extent of 85%. ... 

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... 

The published syntheses of thiophenes include reports on 2-aminothiophene-3-carbonitriles. 10 reacted with ketones and sulfur, catalyzed by aliphatic amines to yield 3675,76 Cyclocondensation of 10 with thioglycolic acid in the presence of a base like sodium ethanolate yielded 2-amino-3-cyano-4-hydroxythiophene (37) and its tautomers. ... 

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>. 

The prior to imiversal synthesis to this kind of product was reported in 1910 by Senary [27] as the multi step reaction of ethyl 4-chloro-2-( ano-3-oxobutanoate (1). After the treatment of 1 with potassium hydrosulfide the reactive sufanyl-substituted intermediate 2 was created, which in the subsequent intramolecular addition of sulfanyl group to cyano group proceeded ethyl 2-amino-4-hydroxythiophene-3-carboxylate (4) in equilibrium with its cyclic tautomer - the appropriate imine 3 (Scheme 1). 

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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