Heterocyclic compounds Pyrimidine Pyrrole

The analytical data obtained, particularly by the PUMA mass spectrometer on board Vega 1 during the flyby, indicate the presence of a large number of linear and cyclic carbon compounds, such as olefins, alkynes, imines, nitriles, aldehydes and carboxylic acids, but also heterocyclic compounds (pyridines, pyrroles, purines and pyrimidines) and some benzene derivatives no amino acids, alcohols or saturated hydrocarbons are, however, present (Kissel and Krueger, 1987 Krueger and Kissel, 1987). 

Heterocyclic amines are compounds that contain one or more nitrogen atoms as part of a ring. Saturated heterocyclic amines usually have the same chemistry as their open-chain analogs, but unsaturated heterocycles such as pyrrole, imidazole, pyridine, and pyrimidine are aromatic. All four are unusually stable, and all undergo aromatic substitution on reaction with electrophiles. Pyrrole is nonbasic because its nitrogen lone-pair electrons are part of the aromatic it system. Fused-ring heterocycles such as quinoline, isoquinoline, indole, and purine are also commonly found in biological molecules. 

The foregoing examples show that the nucleophilic attack to nitroarenes at the o>T/ o-position followed by cyclization is a general method for the synthesis of various heterocycles. When nucleophiles have an electrophilic center, heterocyclic compounds are obtained in one step. Ono and coworkers have used the anion derived from ethyl isocyanoacetate as the reactive anion for the preparation of heterocyclic compounds. The carbanion reacts with various nitroarenes to give isoindoles or pyrimidines depending on the structure of nitroarenes (Eqs. 9.56 and 9.57).89 The synthesis of pyrroles is discussed in detail in Chapter 10. 

In a relatively early paper, Orgel et al.,21 in estimating the DE of pyridine, pyrimidine, pyrazine, and pyrrole, pointed out the difficulty in calculating the energy of the classical structure when the structure to be chosen as a reference becomes less obvious. DE data have, however, been reported for a wide range of heterocyclic compounds including phosphole, pyrrole,22 indole,23 indazole,23 tautomeric azoles,22 tetraazapentalenes,24 cyclazine,25-26... 

Hertz, Heinrich R., 488 Heterocyclic compounds. See also Furan Purine Pyridine Pyrimidine Pyrrole... 

Indeed, a variety of heterocyclic compounds, such as thiophenes, dithiophenes, pyrroles, indoles, or carbazoles can be involved as carbon-centered nucleophiles in these reactions to modify the pyrimidine ring (Scheme 31) [120-122]. For instance, it has been shown that 5-bromopyrimidine reacts with dithiophene into the corresponding 5-substituted pyrimidine due to palladium-catalyzed aryl-aryl C-C cross-coupling reaction. On the other hand, 5-bromo-4-dithiophenyl-substituted pyrimidine was prepared from the same starting material through the SH (addition-oxidation) reaction catalyzed by a Lewis acid in the presence of potassium... 

The methods outlined, of course, are readily applicable to a wide variety of substituted heterocycles like the carboxyl, hydroxy and mercapto derivatives of pyridines, pyridine 1-oxides, pyrroles, etc. The application to amines and to diaza compounds such as pyrimidine, where the two centers are basic, is obvious except that now 23 takes the role of the neutral compound, 21 and 22 the roles of the tautomeric first conjugate bases, and 20 the role of the second conjugate base. Extensions to molecules with more than two acidic or basic centers, such as aminonicotinic acid, pyrimidinecarboxylic acids, etc., are obvious although they tend to become algebraically cumbersome, involving (for three centers) three measurable Kg s, four Ay s, and fifteen ideal dissociation constants (A ), a total of twenty-two constants of which seven are independent. 

As a result of this first report, a large number of compounds containing an isocyclic or a heterocyclic ring fused tc the steroid skeleton were prepared and tested for androgenic and anabolic activity. Included are steroidal isoxazoles [205], thiazoles [94], pyrroles [206], pyrimidines [207,208], oxazines [209], thiazenone [92], quinoline [107], pyridine [122], and furazane [121], all prepared by the fusion of the heterocyclic ring to ring A. Several bis heterocyclic steroids were also prepared by... 

These compounds satisfy the criteria for aromaticity (planar, cyclic n system, and the Huckel number of 4n -I- 2 71 electrons) pyrrole, imidazole, indole, pyridine, 2-methylpyridine, pyrimidine, and purine. The systems with 6 7i electrons are pyrrole, imidazole, pyridine, 2-methylpyridine, and pyrimidine. The systems with 10 7i electrons are indole and purine. The other nitrogen heterocycles shown are not aromatic because they do not have cyclic 7i systems. 

Simple unsubstituted monocycles such as pyridine, pyrazine, pyrimidine, pyridazine and pyrrole show little or negligible binding to either enzyme [3, 10, 173], However, we have shown that fusion or substitution of a phenyl group significantly increases the affinity of the compounds towards aldehyde oxidase, and in some cases the heterocycles are substrates for xanthine oxidase (Table 3.6) [50, 173]. Furthermore, studies with compounds containing a... 

The MM3 force field has been extended by Allinger and co-workers to cover aromatic heterocycles of the pyridine and pyrrole types <93JA11906>. Structures (32 compounds), dipole moments (35 compounds), heats of formation (35 compounds), and vibrational spectra (11 compounds) were examined. The results are good for structure and fair for the other items resonance energies were reported for the series benzene (17.79 kcal mol ), pyridine (17.02 kcal mol ), pyridazine (14.35 kcal mol ), pyrazine (17.01 kcal mol ), pyrimidine (15.60 kcal mol ), 1,3,5-triazine (13.51 kcal mol ), and 1,2,4,5-tetrazine (17.72 kcal mol ). Finally, ab initio studies of the dipole polarizabilities of conjugated molecules have been reported in which monocyclic azines (pyridine, pyridazine, pyrimidine, pyrazine, 5-triazine, and 5-tetrazine) are compared <94JST(304)109>. 

Heterocyclic aromatic compounds contain C and H atoms other than carbon and hydrogen (Fig. 6). For the monocyclic molecules Hiickel s rule is applicable. For example both pyridine and pyrrole contain six ti electrons. Unlike the former the lone pair of the latter is delocalized. Armit and Robinson have shown a connection between the electronic sextet and the heteroaromaticity. Due to the electronegativity difference between carbon and nitrogen the bonds in pyridine are not of equal length and the delocalization is not perfect. Five membered heteroaromatics with oxygen and sulfur are furan and thiophene respectively. Pyrazole/imidazole, triazoles and tetrazoles are five membered heteroaromatics with two, three and four nitrogen atoms respectively. Three important aromatic six membered heterocyclic molecules are pyrimidine, pyrazine and pyridazine. Benzofused... 

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