Keto tautomer

The keto tautomer (211a) is involved in the high electrophilic reactivin-of the C-5 carbonyl group. Thus ring opening has been reported u ith various amino nucleophilic reagents. 

IR spectroscopy has been particularly helpful in detecting the presence of keto tautomers of the hydroxy heterocycles discussed in Section 3.01.6. Some typical frequencies for such compounds are indicated in Figure 4. Here again the doublets observed for some of the carbonyl stretching frequencies have been ascribed to Fermi resonance. 

Photochemical studies on the ring degradation of 3-hydroxy-l,2-benzisoxazole also yielded benzoxazolone, and (40), (41) and (42) (Scheme 14) were believed to be potential intermediates. Low temperature IR measurements indicated the presence of (42) during the photochemical reaction (73JA919, 71DIS(B)4483, 71JOC1088). Sensitization studies indicate that the rearrangement is predominantly a triplet reaction, and the keto tautomer is believed to be the key orientation for the photolysis. 

An ipso attack on the fluorine carbon position of 4-fIuorophenol at -40 °C affords 4-fluoro-4-nitrocyclohexa-2 5-dienone in addtion to 2-nitrophenol The cyclodienone slowly isomenzes to the 2-nitrophenol Although ipso nitration on 4-fluorophenyl acetate furnishes the same cyclodienone the major by-product is 4 fluoro-2,6-dinitrophenol [25] Under similar conditions, 4-fluoroanisole pnmar ily yields the 2-nitro isomer and 6% of the cyclodienone The isolated 2 nitro isomer IS postulated to form by attack of the nitromum ion ipso to the fluorine with concomitant capture of the incipient carbocation by acetic acid Loss of the elements of methyl acetate follows The nitrodienone, being the keto tautomer of the nitrophenol, aromatizes to the isolated product [26] (equation 20) Intramolecular capture of the intermediate carbocation occurs in nitration of 2-(4-fluorophenoxy)-2-methyIpropanoic acid at low temperature to give the spiro products 3 3-di-methyl-8 fluoro 8 nitro-1,4 dioxaspiro[4 5]deca 6,9 dien 2 one and the 10-nitro isomer [2d] (equation 21)... 

The aromaticity of the pyrimidine and purine ring systems and the electron-rich nature of their —OH and —NHg substituents endow them with the capacity to undergo keto-enol tautomeric shifts. That is, pyrimidines and purines exist as tautomeric pairs, as shown in Figure 11.6 for uracil. The keto tautomer is called a lactam, whereas the enol form is a lactim. The lactam form vastly predominates at neutral pH. In other words, pA) values for ring nitrogen atoms 1 and 3 in uracil are greater than 8 (the pAl, value for N-3 is 9.5) (Table 11.1). 

There are at least two different conformers of 3-hydroxyfuran 18a,b (Scheme 8). The energy difference is calculated to be 0.4 kcal/mol. According to DFT calculations the keto tautomer 19 is 12 kcal/mol more stable than the 3-hydroxyfuran 18b (99UP1). If a carbonyl substituent is present... 

A solution whieh eontained ca. 95% of the O-deuterated 3-hydroxyfuran 22 was generated from the trimethylsilyl ether in [De]-DMS0/D20 with DCl at 32°C. After several hours it was eonverted into the keto tautomer 23 deulerated at position 2 (Seheme 9). In all solvents used (CCI4, [DgjDMSO, [Dg]aeetone, CD3OD) no detectable amount of the enol was present at equilibrium (89JA5346). 

Several 2-hydroxybenzofuran-3-earboxylates have been formulated as keto tautomers [78S66 79JCS(P1)2382 93JOC3245]. 3-Aeetylnaphtho[l,2-h]furan-2-(3//)-one and 3-aeetylnaphtho[2,3-h]furan-2-(3//)-one have also been formulated as keto tautomers (Seheme 11) (87CC1150). 

Naphtho[2,l-h]furan-2-(3 -one 28 has been described as a keto tautomer (91JA2301). Naphtho[l,2-h]furan-3-(2//)-ones of type 29 (R = H, Me, Et, Pr, pentyl, heptyl) show keto-enol tautomerism with the enol form predominating (88RRC917). 

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)... 

Aeeording to the IR speetra (neat), nitriles 63a,b exist as 3-thiolene-2-ones 64a,b. For = Ph, R = FI, in CDCI3 solution only the keto tautomer... 

COCH=CHPh) have been formulated as enols (79LA965 81CC118). In some cases mixtures of enol and oxo forms have been observed (84CCC603). Aldimines of type 67 exist predominantly as keto tautomers 68 (74JPR971). 

Ii) the earlier literature there were conflicting reports whether 3-hydroxybenzothiophene 71 (R = H) or its keto tautomer 72 is more stable. Later, this equilibrium was investigated in detail (76AHCS1, p. 235). The... 

NMR spectra of thiophene 77 indicate a small amount (8.4% in CS2) of the second keto tautomer 78. The enol tautomer 76 eould not be detected [78JCS(P1)292]. 

Indoxyl 122 (prepared from the corresponding 0,A-diacetate) exists in the solid state as keto tautomer (as confirmed by IR spectrum) (65CC381). Analysis of its solution in [DgjDMSO showed the presence only of the keto form 122 which, over a period of 24 h, converts to the enol 123 (R = H) (>90%). 

The 0,N-dideuterated enol was formed by hydrolysis of the O-trimethylsilyl ether 123 (R = TMS) (in 80% [D6]DMSO/20% D2O with 5. lO " M DCl). N-Methylindoxyl (formed by hydrolysis of its acetate) exists in the solid state as a mixture of the enol and the keto tautomers (34% enol/66% keto). The NMR spectrum of freshly prepared solution in DMSO demonstrated signals of both enol and keto forms. However, at equilibrium (reached in 18 h at RT) the ratio of enol to ketone depends strongly on the polarity of the solvent used thus, in [Dg]DMSO the tautomeric mixture contains 92% enol, while in CDCI3 the keto form predominates (97%). A solution with 100% enol could be generated by hydrolysis of its O-trimethylsilyl ether [conditions 80% [Dfi]DMSO/20% D2O with 5 10" M DCl at 32°C (86TL3275 87PAC1577 88TL250)]. 

Armulated thiophenes of types 195 and 197 (A benzo, naphtho) were studied concerning keto-enol tautomerism. The ring fusion has a remarkable influence upon these equilibria. Whereas for the c-fused thiophenes 197 only keto tautomers were present, for h-fused derivatives 195 also the enol forms 196 were found (the equilibria are solvent dependent) (82JOC705). 

DFT and post-Hartree-Fock ab initio studies on the different tautomers and rotamers of 2-hydroxy- (94) and 2,3-dihydroxypyrazine (95) indicate that the former species is stabilized by about -3 kcal/mol with respect to its keto tautomer in the gas phase [99JST229]. In solution the opposite appears to be true. For 95, the hydroxyoxo 95b and diketo tautomers 95c are most stable in the gas phase (Scheme 61). 

Mechanism of base-catalyzed enol formation. The intermediate enolate ion, a resonance hybrid of two forms, can be protonated either on carbon to regenerate the starting keto tautomer or on oxygen to give an enol. 

Table 7.3 shows the concentrations of 1-5 that result in 50% growth inhibition (GI50) of five human cancer cell lines. Inspection of these data reveals that cytostatic activity of 1 and 3-5 depends on the thermodynamic favorability of the quinone methide species compared to the corresponding keto form. The most cytostatic prekinamycins 1 and 5 are associated with the thermodynamically stable quinone methides. In contrast, the inactive prekinamycins 3 and 4 are associated with thermodynamically stable keto tautomers. The exception is prekinamycin 2, which is cytostatic and possesses a relatively stable keto tautomer 3 compared to its quinone methide. Although the AE value for quinone methide tautomerization can predict cytostatic properties, prekinamycin 2 shows that there must be other factors determining biological activity. 

Seminal studies on the dynamics of proton transfer in the triplet manifold have been performed on HBO [109]. It was found that in the triplet states of HBO, the proton transfer between the enol and keto tautomers is reversible because the two (enol and keto) triplet states are accidentally isoenergetic. In addition, the rate constant is as slow as milliseconds at 100 K. The results of much slower proton transfer dynamics in the triplet manifold are consistent with the earlier summarization of ESIPT molecules. Based on the steady-state absorption and emission spectroscopy, the changes of pKa between the ground and excited states, and hence the thermodynamics of ESIPT, can be deduced by a Forster cycle [65]. Accordingly, compared to the pKa in the ground state, the decrease of pKa in the... 

Under similar conditions, reactions between pyrrolidine derivatives 632 and MTAD proceed much more slowly and less cleanly with formation of a polymeric material. When the reaction is stopped before 50% conversion is reached, starting compound 632 is isolated as the main component (c. 40%) and compound 637 as a minor product (10-14%). Mechanistically, the most difficult problem lies in the fact that a reduction step has to be involved and no particular reduction agent is present. A proposed mechanism is shown in Scheme 103. The pathway includes a Cannizzaro-type hydride transfer between dipole 633 and product 634 (keto tautomer), resulting in the formation of the iminium derivative 635, which might be responsible for the polymeric material, and hydroxy derivative 636, the direct precursor of the final products 637. The low experimental yield of 637 could be explained by this mechanism <2003EJ01438>. 

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