Pyrimidines aromaticity

Ethoxybutadiene-l,l-dicarbonitriles 11 are used as malonaldehyde equivalents. In a vinylic substitution reaction with the nucleophilic 5-position of 2,6-diaminopyrimidin-4(3i/)-one, the ethoxy group is replaced and the resultant intermediate cyclizes to a dihydropyrido[2,3-d]pyrimidine. Aromatization in the last step then occurs by loss of malononitrile to yield 12.227... 

The process starts from a Knovengol condensation of ethyl isobutyryl acetate with 4-fluorobenzaldehyde. The reaction of S -methyl isothiourea sulfate with a,P-unsaturated ketone followed by oxidation with DDQ gives 2-(methylthio)pyrimidine. This intermediate was further oxidized by w-CPBA to yield 2-(methylsulfonyl)pyrimidine. Aromatic substitution with methyl amine and sulfonylation afford methanesulfonamide derivative. The required alcohol can be synthesized by DIBAL reduction of the corresponding ester as... 

Nucleic acids are acidic substances present m the nuclei of cells and were known long before anyone suspected they were the primary substances involved m the storage transmission and processing of genetic information There are two kinds of nucleic acids ribonucleic acid (RNA) and deoxyribonucleic acid (DNA) Both are complicated biopolymers based on three structural units a carbohydrate a phosphate ester linkage between carbohydrates and a heterocyclic aromatic compound The heterocyclic aro matic compounds are referred to as purine and pyrimidine bases We 11 begin with them and follow the structural thread... 

Two nitrogen containing heterocyclic aromatic compounds—pyrimidine and purine— are the parents of the bases that constitute a key structural unit of nucleic acids... 

Both pynmidme and purine are planar You will see how important this flat shape is when we consider the structure of nucleic acids In terms of their chemistry pyrimidine and purine resemble pyndme They are weak bases and relatively unreactive toward elec trophilic aromatic substitution... 

Section 28 1 Many biologically important compounds are related to the heterocyclic aromatic compounds pyrimidine and purine... 

Pyranose form (Section 25 7) Six membered ring ansing via cyclic hemiacetal formation between the carbonyl group and a hydroxyl group of a carbohydrate Pyrimidine (Section 28 1) The heterocyclic aromatic com pound... 

Electron-density calculations for quinazoline (which has no symmetry) vary markedly with the method used. The diagram (6) has the same bases as that given for pyrimidine above it will be observed that the 2- and 4-positions in quinazoline are comparable with the corresponding positions in pyrimidine and that the aromatic carbon atoms (C-5-C-8) in quinazoline are roughly comparable with C-5 in pyrimidine (67MI21300). The dipole moment of quinazoline does not appear to have been measured, but that of 2-methylquinazo-line is 2.2 D. 

Much of the reactivity shown by the ring atoms and substituents of pyrimidine is akin to that of the corresponding parts of 1,3-dinitrobenzene and 3-nitropyridine. This arises from the quantitatively similar electron-withdrawing effects of doubly-bound ring nitrogen atoms and of nitro groups in reducing sharply the aromaticity of the cyclic system. 

The phenomenon of 5-hydroxymethylation is a standard case of electrophilic attack. Thus uracil (83 R = H) and paraformaldehyde in aqueous alkali furnish 5-hydroj(ymethyl-pyrimidine-2,4(l//,3//)-dione (83 R = CH20H) in good yield (59JA2521). Aromatic aldehydes react differentiy to yield 5-benzylidene derivatives of, for example, 1-methylbar-bituric acid (78CC764). 

Despite considerable localization of tt-electrons at the nitrogen atoms of pyrimidine, the ring system is still sufficiently aromatic to possess substantial stability. This is a great advantage in the primary synthesis of pyrimidines, in the synthesis of pyrimidines from the breakdown or modification of other heterocyclic systems and in the myriad of metatheses required to synthesize specifically substituted pyrimidines. 

The other main reaction in this class is the Dieckmann-type cyclization of the intermediates (163) from 4(6)-halo-5-ethoxycarbonylpyrimidines with AC-substituted /3-alanine esters and nitriles, and related compounds, to give 5,6,7,8-tetrahydro-5-oxopyrido[2,3-[Pg.221]

Aromatic aldehydes give 2-aryl-4-oxo derivatives (181) in the presence of concentrated sulfuric acid (70EGP73039), whilst pyrimidine derivatives (182) give octahydropyrido[4,3-with formaldehyde (e.g. 66M52). A similar reaction is observed with 6-methylpyrimidinones (e.g. 70M1415). 

The corresponding saturated dialkylamino ketones (Mannich bases) have also been used to provide 5,6-dihydro derivatives, which are oxidized in air to aromatic pyrido[2,3-[Pg.229]

Heavily fluonnated aminobenzenes, pyridines, and pyrimidines are diazotized in strong-acid media Solid sodium nitrite added directly to the fluonnated amine dissolved in 80% hydrofluonc acid, anhydrous hydrogen fluoride, or (1 1 wt/wt) 98% sulfuric acid in (86 14 wt/wt) acetic and propionic acids affords the electrophilic fluoroarenediazonium ion Addition of an electron rich aromatic to the resultant diazonium solution gives the fluoroareneazo compound [10 II] (equa tions 9 and 10)... 

Typical perfluoroalkylated aromatic derivatives prepared via this type of reaction are illustrated in Table 6. This methodology has been used for the preparation 5-(perfluoroalkyl)pyrimidines [194], heptafluoroisopropylated aromatics... 

The pyrimidine ring system is planar, while the purine system deviates somewhat from planarity in having a slight pucker between its imidazole and pyrimidine portions. Both are relatively insoluble in water, as might be expected from their pronounced aromatic character. 

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). 

Another property of pyrimidines and purines is their strong absorbance of ultraviolet (UV) light, which is also a consequence of the aromaticity of their heterocyclic ring structures. Figure 11.8 shows characteristic absorption spectra of several of the common bases of nucleic acids—adenine, uracil, cytosine, and guanine—in their nucleotide forms AMP, UMP, CMP, and GMP (see Section 11.4). This property is particularly useful in quantitative and qualitative analysis of nucleotides and nucleic acids. 

The preparations of over two hundred tetrahydro- and octahydro-pyrido[4,3-d]pyrimidines from piperidines or from purely aliphatic starting materials are described in the patent literature. Fully aromatic examples of the system have been prepared from pyridines and pyrimidines. 

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