Membered Aromatic Derivatives

There are two distinct classes of compounds that fit the criteria mentioned above alkene-functionalized chalcone derivatives (Fig. IB) and enone-functionalized chalcone derivatives (Fig. 1C). Within each class, both aromatic and non-aromatic compounds exist. Those compounds functionalized at the alkene include i) 3-membered heterocycles, e.g., epoxide and aziri-dine compounds, ii) 5-membered aromatic derivatives including fused and non-fused compounds, and iii) 6-membered aromatic pyrazine compounds. The enone-functionalized compounds include i) 5-membered aromatics such as pyrazole and isoxazole compounds, ii) 5-membered non-aromatic compounds for example pyrazolines and isoxazolines, and iii) 6-membered non-aromatics where a discussion of heterocyclic and non-heterocyclic compounds will be given for completeness. 

Tobacco Alkaloids. The relatively small number of alkaloids derived from nicotinic acid (27) (the tobacco alkaloids) are obtained from plants of significant commercial value and have been extensively studied. They are distinguished from the bases derived from ornithine (23) and, in particular, lysine (24), since the six-membered aromatic substituted pyridine nucleus common to these bases apparendy is not derived from (24). 

Aromatic derivatives of cyclotriphosphazenes, rigid six-membered ring systems built on a framework of alternating P and N atoms, provide one of the more beautiful early examples of hosts that form channel-type clathrates and can be useful for molecular separations 32,42>, Although these clathrate systems were discovered by accident, the conclusions that emerged from their investigation have been extremely helpful for the molecular design of other potential host molecules. 

Another interesting class of five-membered aromatic heterocycles has recently been published by Tron et al. [54]. These compounds have biological activity in the nM range. An example of the formation of these furazan (1,2,5-oxadiazole) derivatives is shown in Scheme 9. The diol 50 was oxidized to the diketone 51 using TEMPO and sodium hypochlorite. Transformation to the bisoxime 52 was performed in an excess of hydroxylamine hydrochloride and pyridine at high temperature for several days. Basic dehydration of 52 formed two products (53a and b). A Mitsunobu reaction was then employed using toluene as solvent to form compound 53b in 24% yield. 

Boron. Five-membered aromatic rings containing a boron atom and two X-type heteroatoms display six jr-electrons and are consequently aromatic. Such systems are 1,3,2-dioxaborole (78) and its benzo derivative (79, Scheme 40).126-129 5,6-Diamino-1,3-... 

It is also possible to construct seven-membered aromatic heterocycles with a jr-electron decet if the heteroatoms have sufficient electronegativity to produce seven bonding orbitals with 10 jr-electrons, as in compounds of type 209 (Scheme 79). For thio derivative 209 (X = S, Scheme 79), lH NMR data show deshielded NH protons compared to the system with X = CH2, a fact which was explained by aromatic delocalization.249... 

Review papers have covered (81RCR336 84KGS579) the field of rotational isomerism in carbonyl-containing derivatives of five-membered aromatic heterocycles. This article aims to report a critical account of the results appearing in the literature concerning conformational information on heterocyclic acyl derivatives. 

CoNTORMER Populations and Free Energy of Activation for Acyl Derivatives of Five-membered Aromatic Heterocycles ... 

Most of the conformational properties of the acyl derivatives originate in the high polarity of the C=0 bond. Comparative studies have been reported between several chemical functionalities containing the C=0 moiety, i.e., besides heterocyclic aldehydes and ketones, acyl halides, esters, amides, and urethanes, which have different electronic character. Furthermore, the behavior of the C=0 group has been compared, with regard to its conformational properties, to C=C and C=N double bonds in vinyl derivatives, oximes, and azomethines. Most of the results relative to five-membered aromatic heterocycles have been discussed previously (81RCR336 84KGS579). 

More accurate investigations on acyl derivatives of five-membered aromatic heterocycles need to be carried out, to replace earlier results and to provide homogeneous sets of energy differences between conformers and energy barriers, if possible, also in different physical conditions. For the 3-formyl and, in general, 3-acyl derivatives, the influence of solvent polarity must be more carefully examined. 

Because of the enhanced rigidity of the higher-membered heteroannulenes, e.g. (36), imparted chiefly by the presence of properly positioned trans double bonds, these frames are generally less thermally labile than their heteronin counterparts although here too aromatic derivatives are substantially more heat resistant than their polyenic relatives. It was noted, for example (75PAC(44)69l), that while parent aza[13]annulene (37a) is thermally stable at 56 °C, its polyenic acetamide (36a) readily rearranges ( i/2< 1 h) under these conditions to what is believed to be a tricyclic isomer (96). 

Bromination The five-membered aromatic heterocycles are all more reactive toward electrophiles than benzene is, and the reactivity is similar to that of phenol. These compounds undergo electrophilic bromination. However, reaction rates vary considerably, and for pyrrole, furan and thiophene the rates are 5.6 x 10, 1.2 x 10 and 1.00, respectively. While unsubstituted five-membered aromatic heterocycles produce a mixture of bromo-derivatives, e.g. bromothiphenes, substituted heterocycles produce a single product. 

The five-membered aromatic heterocycles pyrrole (5), furan (6) and thiophene (7) are formally derived from cyclopentadienyl anion by replacement of one CH group with NH, O or S, each of which can contribute two p-electrons to the aromatic ir-electron 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 (5), (6) and (7) by further replacement of CH groups with N, 0+ or S+. 

In the discussion of structural and spectroscopic aspects of thiophenes to follow, the reader does well to bear in mind that in fact aromaticity is a hallmark of thiophenes that dominates their properties and governs their reactions. Moreover, thiophene stands as uniquely aromatic among the five-membered heterocycles. In concrete terms this means that not only does thiophene undergo the reactions and have the physical and spectral properties associated with the concept of aromaticity, but that this aromatic character is steadfastly maintained through all manners of transformations including fusion with other aromatic rings. This attachment of substituents or fusion with other rings spawns thousands of aromatic derivatives. 

Although the number of Diels-Alder cycloadditions with open-chain and alicyclic dienes is very large, the number of examples with aromatic heterocyclic compounds is relatively small. The introduction of a vinyl group as a substituent onto a heterocycle increases the number of possibilities of reaction. This new possibility, however attractive for synthetic purposes, is successful, with a few exceptions, only with 7r-excessive five-membered heterocyclic derivatives. As is usual in this kind of reaction, Michael additions, ene reactions, [2 + 2]-cycloadditions, and polymerization compete with the Diels-Alder cycloaddition. 

The diazines (pyridazine, pyrimidine, and pyrazine) are six-membered aromatic heterocycles that have two nitrogens in the ring. Cytosine, thymine, and uracil are derivatives of pyrimidine that are important bases in nucleic acids (DNA and RNA). Heterocyclic analogs of the aromatic hydrocarbon naphthalene include pteridines, which have four nitrogens in the rings. Naturally occurring pteridine derivatives include xanthopterin (a pigment) and folic acid (a vitamin). Methotrexate is a pteridine used in cancer chemotherapy. 

Aromatic-substituted imines, especially those having electron-donating groups in the /wzz-position, undergo a [2+2] cycloaddition reaction with aryl isocyanates <1969CB938, 1978T101>. In the presence of an excess of azomethine, the six-membered triazine derivative is the exclusive product <1970MI149>. 

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