Five-membered Heterocycles containing One Heteroatom Pyrrole, Furan and Thiophene

Five-membered Heterocycles containing One Heteroatom Pyrrole, Furan and Thiophene... 

The rates of nitration of isothiazole (and its 3- and 5-methyl derivatives) have been measured. While isothiazole and its 3- and 5-methyl derivatives are nitrated as free bases, the 3,5-dimethyl-compound is nitrated as the conjugate acid. Isothiazoles are nitrated in the 4 position 10 times slower than benzene. The order of reactivity for nitration is pyrazole > isothiazole > isoxazole, in contrast to that of five-membered heterocycles containing one heteroatom, which for trifluoroacetylation is pyrrole > furan > thiophen. ... 

The preparation of five-membered rings in solid-phase organic chemistry has been reported in several publications. Versatile syntheses of these heterocycles with different numbers and kinds of heteroatoms have been described. The synthesis of five-membered rings containing one nitrogen atom (Fig. 3.6) as pyrrolidines (231) [311-316] pyrroles (232) [317-320] pyrrolidinones (233) [321-323] pyr-rolinones (234) [324—326] 2,5-pyrrolidinediones (235) [327-329] 2,4-pyrrolidine-diones (236) [330-332] 2,5-pyrrolinediones (237) [333] or heterocycles with one oxygen or one sulfur atom like tetrahydrofurans (238) [334—336] 2,5-dihydrofurans (239) [337], furans (240) [338, 339], yS-lactones (241) [340-343], 2,5-dihydrofura-nones (242) [344] (Scheme 3.35) and thiophenes (243) [345, 346] can be accomplished on solid supports. 

We have looked at the five-membered aromatic heterocycles pyrrole, furan and thiophene in Section 11.5. Introduction of a second heteroatom creates azoles. This name immediately suggests that nitrogen is one of the heteroatoms. As soon as we consider valencies, we discover that in order to draw a five-membered aromatic heterocycle with two heteroatoms, it must contain nitrogen A neutral oxygen or sulfm atom can have only two bonds, and we cannot, therefore, have more than one of these atoms in any aromatic heterocycle. On the other hand, there is potential for having as many nitrogens as we like in an aromatic ring. 

Pyrrole, furan, and thiophene are five-membered-ring heterocycles. Each has three pairs of delocalized rr electrons Two of the pairs are shown as rr bonds, and one pair is shown as a lone pair on the heteroatom. Furan and thiophene have a second lone pair that is not part of the rr cloud. These electrons are in an sp orbital perpendicular to the p orbitals. Pyrrole, furan, and thiophene are aromatic because they are cyclic and planar, every carbon in the ring has a p orbital, and the tt cloud contains three pairs of tt electrons (Sections 15.1 and 15.3). 

For the sake of simplicity, the term pyrrole-derived will be used to refer to any macrocycle that contains any combination of five-membered, one-heteroatom-containing cycles, including pyrrole, furan, thiophene, and related systems. According to common convention, the 2- and 5-positions of these five-membered heterocycles will typically be referred to as the alpha (a) positions, while the 3- and 4-... 

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