Covalent hydration pyrimidines

In aqueous alkaline conditions with chloroacetic acid the pyrido[4,3- f]pyrimidinethione (80) undergoes facile ring opening, attributed to the resonance stabilization of a delocalized covalent hydrate dianion intermediate (81) (82). Pyrido[2,3- f]pyrimidine-4-thiones (and... 

P3Timidines, and pyrido[4,3-< ]pyrimidines. The experimentally determined values have been used for studies of covalent hydration, structural assignments, - and tautomerism. -... 

Nuclear magnetic resonance spectra of all four parent compounds have been measured and analyzed.The powerful potentialities of NMR as a tool in the study of covalent hydration, tautomerism, or protonation have, however, as yet received no consideration for the pyridopyrimidines. NMR spectra have been used to distinguish between pyrido[3,2-d]pyrimidines. and isomeric N-bridgehead compounds such as pyrimido[l,2- ]pyrimidines and in several other structural assignments (cf. 74 and 75). 

In common with other fused pyrimidines, the pyridopyrimidines are susceptible to the nucleophilic addition of water across the 3,4-bond. This is the phenomenon of covalent hydration... 

The parent compounds undergo facile hydrolysis to aminoaldehydes subsequent to the covalent hydration and reversible ring-opening as described above for pyrido[4,3-d]pjrrimidines (Section IV, B). 2-(3-Pyridyl)pyTido[2,3-d]pyrimidine undergoes hydrolysis to yield 2-aminonicotinaldehyde and nicotinamide when treated with N—HCl under reflux for 3 hours. This mechanism also probably involves a covalent hydrate. 2-Methylpyrido[4,3-d]pyrimidin-4(3H)-one, although much more stable than the parent compound, is readily hydrolyzed with dilute acid, whereas the isomeric compounds from the other three systems are stable under such conditions. 

Oxidations of pyridopyrimidines are rare, but the covalent hydrates of the parent compounds undergo oxidation with hydrogen peroxide to yield the corresponding pyridopyrimidin-4(3 T)-ones. Dehydrogenation of dihydropyrido[2,3-(i]pyrimidines by means of palladized charcoal, rhodium on alumina, or 2,3-diehloro-5,6-dicyano-p-benzo-quinone (DDQ) to yield the aromatic derivatives have been reported. Thus, 7-amino-5,6-dihydro-1,3-diethylpyrido[2,3-d]-pyri-midine-2,4(lif,3f/)-dione (177) is aromatized (178) when treated with palladized charcoal in refluxing toluene for 24 hours. 

The rate-acidity profile for pyrimidin-2-one indicated reaction on the free base but since the derived second-order rate coefficient is 104 times greater than that for 2-pyridone, and the acidity dependence in the H0 region was also greater, the slope of log kt versus —H0 plot being 0.45, cf. 0.15 for 2-pyridone reaction was, therefore, postulated as occurring via a covalent hydrate, hydration taking place at the 4 position. Methyl substitution increased the rate as expected and N-methyl substitution produced a larger effect than 4,6-dimethyl substitution and this may be due to alteration of the amount of covalent hydration at equilibrium. The data... 

MI33>. Covalent hydration of pyrimido[4,5- pyrimidines was reported in CHEC-II(1996) <1996CHEC-II(7)737> covalent hydration across the 7-8 bond of 6- and 8-methylated species 68 and 69 has been investigated in detail <2003EJM719>. 

A fused benzene ring has little effect on the pKa values in the cases of quinoxaline (ca. 0.6) and cinnoline (2.6). Quinazoline has an apparent pAfa of 3.3 which makes it a much stronger base than pyrimidine, but this is due to covalent hydration of the quinazolinium cation (see Section 3.2.1.6.3) the true anhydrous pK.d for equilibrium between the anhydrous cation and anhydrous neutral species of quinazoline is 1.95 (76AHC(20)128). 

Pyrimidin-2-one exchanges its 5-hydrogen much faster than pyridin-2-one. However, this is due to the existence of a small proportion of the covalent hydrate (106) which undergoes rapid exchange. 

Increasing numbers of nitrogen atoms increase not only the kinetic susceptibility toward attack but also the thermodynamic stability of the adducts. Reversible covalent hydration of C = N bonds has been observed in a number of heterocyclic compounds (76AHC(20)117). Pyrimidines with electron-withdrawing groups and most quinazolines show this phenomenon of covalent hydration . Thus, in aqueous solution the cation of 5-nitropyrimidine exists as (164) and quinazoline cation largely as (165). These cations possess amidinium cation resonance. The neutral pteridine molecule is covalently hydrated in aqueous solution. Solvent isotope effects on the equilibria of mono- (166) and dihydration (167) of neutral pteridine as followed by NMR are near unity (83JOC2280). The cation of 1,4,5,8-tetraazanaphthalene exists as a bis-covalent hydrate (168). 

The rearrangement of the triazolo[4,3-c]pyrimidines, e.g., 24, to their [2,3-c) isomers has been hypothesized as going through a neutral covalent hydrate followed by ring fission.35 Kinetic evidence has been... 

Not until 1967 was covalent hydration found in a single-ring aromatic nucleus, but several examples are now known. The cation of 5-nitro-pyrimidine (also its 2-methyl and 2-benzyl derivatives) adds a molecule... 

A parallel study of aqueous bromination of pyrimidin-4(3//)-one and its /V-methyl derivatives also pointed to an addition-elimination process involving cationic intermediates. The kinetic results for these substrates differed from those of 39 (in which the pseudo bases dehydrate as neutral molecules) in that the intermediates dehydrated in cationic forms (79JOC3256). Again, the covalent hydrates, though present to only a minor extent (—0.0003%), were the reactive species in the bromination process. Pyrimidin-4(3//)-one, as its covalent hydrate, reacts 600 times faster than it does itself the rate enhancement is even greater O 104) for the 2-isomer, which exhibits a higher degree (—0.05%) of covalent hydration. 

Albert, A., 4-Amino-1,2,3-triazoles, 40, 129 The Chemistry of 8-Azapurines( 1,2,3-Triazolo[4,5-d]pyrimidines), 39, 117 Annelation of a Pyrimidine Ring to an Existing Ring, 32, 1 Covalent Hydration in Nitrogen Heterocycles, 20, 117. 

Covalent hydration can be important (e.g., in certain pyrimidines exchange can occur via covalently hydrated species). 

---