6-Methoxy tautomer

Claramunt et al. [22] used a H and 13C NMR to study the tautomer-isim of omeprazole in solution. The tautomeric equilibrium constant, KT = 0.59 in tetrahydrofuran at 195 K, is in favor of the 6-methoxy tautomer. The assignment of the signals was made by comparison with its two N-methyl derivatives in acetone-d6 and through theoretical calculations of the absolute shieldings (GIAO/DFT/6-3111++G ). 

Claramunt et al. [23] recorded the 13C and 15N CPMAS spectra of solid sample of omeprazole and all signals assigned. The sample consists uniquely of the 6-methoxy tautomer. 

In 2007, Bhatt and Desiraju reported that the five different solid forms of opremazole have varying proportions of the 5-methoxy and 6-methoxy tautomers. Only one form is the pure 6-methoxy tautomer, while all other forms are mixture of 5- and 6-methoxy tautomers ranging from pure to a 15 85 mixture of 5-methoxy- 6-methoxy opremazole (2007CC2057). Solid-solution hardening of molecular crystals in connection with tautomeric polymorphs of opremazole has been discussed (2015JA1794). 

In 2007, Bhatt and Desiraju [27] reported that in the solid state omeprazole yields five different forms that were described as tautomeric polymorphs. One of the forms, called form I, contains exclusively 6-methoxy tautomer while the remaining four forms have different proportions of the 5-methoxy (Tl) and 6-methoxy (T2) tautomers (Figure 13.1). Namely, form II comprises Tl and T2 tautomers in a 8 92 ratio form III in a 10 90 ratio form IV in a 12 88 ratio and form V in a 15 85 ratio. It is interesting to note that except those, other ratios of Tl and T2 tautomers in the solid state have not been observed [104]. All five forms crystallize in the triclinic space group P-1 with one molecule per asymmetric unit... 

Figure 13.5 Centrosymmetric dimers of omeprazole molecules form via N-H- -0(=S) hydrogen bonds while creating a R j(IO) motif, (a) In form I, dimers contain only 6-methoxy tautomer (T2) and (b) in forms II-V, dimers comprise 6-methoxy (T2) and 5-methoxy (T1) tautomers. 5-Methoxy groups in (b) are marked by squares.

While dealing with imidazoles, an important characteristic is their annular tautomerism. A tautomeric equilibrium for many imidazoles is rapidly achieved at room temperature. In some tautomeric pairs, though, one tautomer often predominates over the other. For instance, 4(5)-bromoimidazole favors the 4-bromo-tautomer in a 30 1 ratio, whereas 4(5)-nitroimidazole exists predominantly as the 4-nitro tautomer (700 1) [11]. 4(5)-Methoxyimidazole has a ratio of 2.5 1 for the 4- and 5-methoxy tautomers. 

Omeprazole is a benzimidazole derivative used as an antiulcer drug [102]. In solution, it exists as a mixture of two tautomeric forms, 5-methoxy (Tl) and 6-methoxy (T2) one, while In the gas phase 5-methoxy tautomer (Tl) appears to be slightly more stable (Scheme 13.19) [103]. 

The O-alkyl derivatives of those A-oxides, which exist partly or entirely as (V-hydroxy tautomers, may be made by primary synthesis (as above) or by alkylation. Thus, 5,5-diethyl-1-hydroxybarbituric acid (936 R = H) with methyl iodide/sodium ethoxide gives the 1-methoxy derivative (936 R = Me) or with benzenesulfonyl chloride/ethoxide it gives the alkylated derivative (936 R = PhS02) (78AJC2517). 

X-Ray crystal structure determinations of l-(aminocarbonyl)-3-methyl-4-methoxy-l//-pyrazol-5(2H)-one 107 (R = H) and l-(phenylaminocar-bonyl)-3-methyl-4-methoxy-l//-pyrazol-5(2H)-one 107 (R = Ph) demonstrated that both molecules exist in the crystal exclusively as NH-CO tautomers (97T5617). The tautomeric form similar to 104b is realized in the crystal of 4,4-dichloro-substituted pyrazolone 108 (93BSB735). 

Bromo-6,7,8,9-tetrahydro-l//-3-benzazepin-2-amine(6) with thiocyanate ion undergoes substitution of bromide to give the thiocyanatotetrahydro-l//-3-benzazepine 7.105 Attempts to replace bromide by azide ion failed, as did diazotization of the amine group with sodium nitrite in 6 M sulfuric acid. Oddly, treatment of the aminobromo compound with sodium borohydride in methanol results not in reduction, but in methoxy-debromination to give the 2-methoxy derivative which, on the basis of HNMR spectral data, is best represented as the 2-imino tautomer 8. 

Irradiation of 4-azidoquinolines in the presence of sodium methoxide gives unstable 5-methoxy-lH-, 4-benzodiazepines 1, which rearrange to the stable 3//-tautomers 2 on further treatment with sodium methoxide.215... 

Photolysis of 3-azidoquinolines 4 in the presence of sodium methoxide gives 3-methoxy-3//-l,4-benzodiazepines 5, which rearrange to the 5//-tautomers 6 on heating with methanolic sodium... 

Azido-3-methoxypyridazines 1 are transformed into 6,7-dimethoxy-477-1,2.5-triazepines 3 by irradiation in the presence of sodium methoxide. The reaction proceeds via the unstable 277-tautomers 2, which were detected by NMR spectroscopy and can be trapped as the 2-acetyl derivatives 4 by adding acetyl chloride to the crude photolysate.371 The synthesis fails for azidopyridazines lacking the 3-methoxy substituent. 

The extranuclear C-nitrosoquinoxalines are typified by 3-(a-methoxycarbonyl-a-nitrosomethyl)-2(l/i)-quinoxalmone (66), made by nitrosation of 3-(methoxy-carbonylmethyl)-2(l/f)-quinoxalmone (65) [AcOH, CI3CO2H, C5H11ONO, 20°C, 3 h 91% spectra suggest that the hydroxyimino tautomer (67) may predominate] and was subsequently reduced to afford 3-(a-amino-a-methoxycarbonylmethyl)-2(l//)-quinoxafinone (68) (PtOa, H2, 1 atm, THF, EtOH, 20°C, 4 h 59%) also by 3-[a-(4-amino-5-methyl-4//-l,2,4-triazol-3-yl)-a-nitrosomethyl]-2(l//)-quinoxa-linone (69, R = NO), prepared by nitrosation of 3-(4-amino-5-methyl-4//-1,2,4-triazol-3-ylmethyl)-2(177)-quinoxalinone (69, R = H) [NaN02 ( 1.25 equiv), AcOH, H2O, no further details 79%]." ... 

Hie reaction below leads to a product, 2-(2 -hydroxy-3 -acetoxyphenylamino)-5-methoxy-l,4-benzoquinone (28), that, in solution, is an equilibrium mixture of tautomers (74). The two tautomers can be crystallized separately, the open-chain form as black crystals, the ring form as yellow ones both decompose at 176°. 

The prototropic tautomerism of 8-azaadenine has been studied theoretically in both the gas phase and aqueous solution by means of ab initio methods. It has been shown that dehydrovaline (399 R =Me, R = H, R = Me), dehydrophenylalanine (399 R = Ph, R, R = H), and dehydropipecolinic acid [399 R R = (CH2)3, R = H] hydrolyse rapidly via the imine tautomer (400) even when the corresponding esters and sodium salts exist as the enamine tautomers. The 3-methoxy-substituted deriva-... 

Polarography has been used (86JOC3542) to determine very small concentrations of the open-chain tautomer of 2,4-dihydroxy-7-methoxy-l,4-benzoxazin-3-one (see 46A in Section II,B,l,b). 

Introduction of a methoxy group (28, R = OMe) into the aryloxy side chain in the series of prostaglandin intermediates 28 has been found [90JCS(P1)751] to affect the ring-chain equilibrium significantly in favor of the cyclic tautomer. In CDCI3, when R = H, Kj = 1, and when R = OMe, Kt = 9. 

The electronic effect of the substituent X on the 2-phenyl ring proved to influence the ring-chain tautomeric equilibria of 2-aryl-l-hydroxy-l,4-dihydro-2//-3,l-benzoxazines 79. While the proportion of the cyclic tautomer B in CDCI3 was 90% for the unsubstituted (X = H) and 70% for the />-methoxy derivative (X = OMe), no cyclic form could be detected in the case of the -dimethylamino compound (X = NMc2). Independently of the substituent X, the tautomeric equilibria of the regioisomeric 2-aryl-3-hydroxy-3,4-dihydro-2//-l,3-benzoxazines likewise contained no detectable amounts of the cyclic forms <1997CJC1830, 1998CJC389>. 

Bulaquine is a mixture of 3 -l-4-6(-methoxy-8-quinolinyl) aminopentyl ethylidenedihydro-2-(3H) furanone and it s tautomers. 

III,D, 1). In spite of this, differences in the spectra of 5-anilino-3-hydroxy- and 3-alkoxy-5-anilino-l,2,4-thiadiazoles suggest that ketonic tautomers of the hydroxy compound contribute to the resultant absorption curve. Similar observations are made with 3-hydroxy-5-phenyl-l,2,4-thiadiazole.122 The spectra of 4-methylpyrimid-2-one and 2-methoxy-4-methylpyrimidine led to similar conclusions.170... 

Cytosines substituted at the amino group by hydroxy, methoxy, or amino groups are known to exist as mixtures of tautomers 21 or 23 and 22 or 24, respectively. The tautomeric properties of these cytosines were... 

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