Heterocycles aromatic with 2 heteroatoms

Heterocycles containing oxygen, nitrogen, or sulfur—atoms that also have at least one lone pair of electrons—can also be aromatic. With heteroatoms, we must always determine whether the lone pair is localized on the heteroatom or part of the delocalized ji system. Two examples, pyridine and pyrrole, illustrate these different possibilities. 

Aromatic carbon-heteroatom coupling reactions with participation and formation of heterocycles 98JCS(P1)2615. 

Heterocyclic systems have played an important role in this historical development. In addition to pyridine and thiophene mentioned earlier, a third heterocyclic system with one heteroatom played a crucial part protonation and methylation of 4//-pyrone were found by J. N. Collie and T. Tickle in 1899 to occur at the exocyclic oxygen atom and not at the oxygen heteroatom, giving a first hint for the jr-electron sextet theory based on the these arguments.36 Therefore, F. Arndt, who proposed in 1924 a mesomeric structure for 4//-pyrone, should also be considered among the pioneers who contributed to the theory of the aromatic sextet.37 These ideas were later refined by Linus Pauling, whose valence bond theory (and the electronegativity, resonance and hybridization concepts) led to results similar to Hiickel s molecular orbital theory.38... 

The species which are unknown and have not been identified as one of the major chemical lump such as alkanes, phenols and aromatics are lumped together as unidentified. However, the species in this lump include saturated and unsaturated cycloalkanes with or without side chains, which resembles the naphthenes, a petroleum refinery product group. A number of well known species in coal liquid are not mentioned in this lumping scheme. Such as heterocyclic compounds with sulfur, nitrogen or oxygen as the heteroatom, and other heteroatora containing species. Some of these compounds appear with aromatics (e.g. thiophenes, quinolines) and with phenols (e.g. aromatic amines), and most of them are lumped with the unidentified species lump. 

The following types of dipolarophiles have been used successfully to synthesize five-membered heterocycles containing three heteroatoms by [3 + 2]-cycloaddition of thiocarbonyl ylides azo compounds, nitroso compounds, sulfur dioxide, and Al-sulfiny-lamines. As was reported by Huisgen and co-workers (91), azodicarboxylates were noted to be superior dipolarophiles in reactions with thiocarbonyl ylides. Differently substituted l,3,4-thiadiazolidine-3,4-dicarboxylates of type 132 have been prepared using aromatic and aliphatic thioketone (5)-methylides (172). Bicyclic products (133) were also obtained using A-phenyl l,2,4-triazoline-3,5-dione (173,174). 

In Section 11.2 peptides based on a variety of aromatic heterocycles are discussed.1 2-21 Some of them are natural products with bioactivities ranging from antibiotics to double stranded DNA intercalators. Heterocyclic systems with five or six atoms, characterized by a single or a combination of N, O, and S heteroatoms, are described. In selected cases reduced, nonaromatic rings are also covered. 

The sixth chapter, Preparation, Structure and Biological Property of Phosphorus Heterocycles with a C-P Ring System by Mitsuji Yamashita presents a very critical review of novel phosphorus heterocycles. The review discusses aliphatic 4-, 5-, 6- and 7-membered C-P-C heterocycles, aromatic C-P-C heterocycles, and various C-P-0 type heterocycles including phospha sugars. Synthetic aspects, structural studies, and the biological properties of these phosphorus heterocycles are also addressed. This chapter may attract the interest of synthetic chemists as well as heterocyclic and heteroatom chemists in the life science fields. 

In intramolecular arylations, a new bond is created between two aromatic moieties of the same molecule or between an aromatic nucleus and an atom of a side-chain. Many intramolecular arylation reactions of homocyclic and heterocyclic aromatic halides have been studied mainly in view of their synthetic applications, and it is not always clear which mechanistic pathway is followed. The reaction may start with homolytic or heterolytic dissociation of the carbon-halogen bond and proceed by attack of the aryl radical or aryl cation on another part of the molecule. Electrocyclization followed by elimination of hydrogen halide is another possibility. Especially when heteroatoms such as nitrogen, sulphur or phosphorus are involved, the initial step may be a nucleophilic attack on the carbon atom bearing the halide atom. 

The five-membered aromatic heterocycles pyrrole 8, furan 9, and thiophene 10 are formally derived from the cyclopentadienyl anion 2 by replacement of one GH group with NH, O, or S, each of which contributes two n-electrons to the aromatic sextet. Heteroatoms of this type have in classical structures only single bonds and are called pyrrole-like. Other five-membered aromatic heterocycles are derived from compounds 8, 9 and 10 by further replacement of CH groups with N, 0+, or S+, e.g., imidazole 15. 

Most of the examples reviewed concentrate on instances in which the C X heteroatom is oxygen, and this reflects the dearth of work that has been reported on other heteroatoms. Thus, although numerous examples of the aromatization of nitrogen heterocycles exist, there is very little pertaining to other systems. This is an area where more exploratory work is needed, especisdly on oxazolines and related heterocycles.Reactions with C=cS compounds are even more rare, presumably because of the ease with which such systems are oxidized under dehydrogenation conditions. Opportunities exist to develop the dehydrogenation of such systems, however, as demonstrated with thioamides which have served as suitable intermediates for the dehydrogenation of otherwise difficult amides. ... 

This chapter considers how aromatic heterocyclic compounds with two or more nitrogen (or other heteroatoms, chiefly O and S) atoms can be made. In particular it deals with the addition of new C-C and C-X bonds to previously prepared heterocycles of this kind. 

We can now look at specific examples, and see how the principles above can lead to the aromatic heterocycles. In the first of the two broad categories, where only C-heteroatom bonds need to be formed, and for the synthesis of five-membered heterocycles, precmsors with two carbonyl groups related 1,4 are required, thus 1,4-diketones react with ammonia or primary amines to give 2,5-disubstituted pyrroles two successive heteroatom-to-carbonyl carbon additions and loss of two molecules of water produce the aromatic ring, though the exact order of these several steps is never certain. 

The reactivity of five membered heterocycles with two heteroatoms as dienes with at least one nitrogen for Diels-Alder reactions is also very low. In fact, there is not much experimental data in this area of research, except for addition of dienophiles to oxazole, better known as the Kondrateva reaction [57]. The main reason for their low reactivity is high heterocycle aromaticity delocalization of molecular x-orbitals that should be part of the cycloaddition reaction. That can be explained from FMO energy difierences between aromatic heterocycles as well as by bond order uniformity of heterocycles with two heteroatoms... 

The other method to determine reactivity for reactions with synchronous concerted cyclic transition state structures is evaluation of the transition state ring aromaticity through bond order deviation. The results of the exo cyclopropene addition to the heterocycles and to cyclopentadiene are presented in Table 33. The higher the sum of bond order deviation from average bond order (x) is, the lower aromatic character the transition state structure has. The most reactive dienophile was cyclopentadiene, followed by furan, and then heterocycles. The most reactive heterocycle with heteroatoms in 1,3-position was 1,3-oxazole as was predicted on the basis of the FMO energy changes (Table 32). The least reactive was 1,3-diazole, as one would expect on the basis of experimental observations. It is very difficult to rely on the transition state structure bond order deviation to determine the experimental feasibility of a reaction but, because SBOD for furan and 1,3-oxadiazole were very similar, one can conclude that the cycloaddition with 1,3-oxadiazole is also experimentally feasible. 

As our computational results presented above demonstrate, it is highly unlikely that heterocycles would be good dienes for Diels-Alder reactions if formation of one or two C-N bonds were involved in the course of the reaction. This automatically eliminates some tautomeric forms of five-membered heterocycles with heteroatoms in 1 and 2 positions as well as five-membered heterocycles with heteroatoms in 1,2,3 and 1,2,5 positions. A major reason for the low reactivity of the heterocycles is because of their high aromaticity. It is obvious that diminishing or eliminating the aromaticity in these heterocycles would make them better dienophiles for Diels-Alder reactions. 

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