Heterocyclics imidazoles

If we copy Nature rather more exactly, the Claisen ester condensation can be carried out under neutral conditions. This requires rather different reagents. The enol component is the magnesium salt of a malonate mono-thiol-ester, while the electrophilic component is an imidazolide—an amide derived from the heterocycle imidazole. Imidazole has a pK of about 7, Imidazolides are therefore very reactive amides, of about the same electrophilic reactivity as thiol esters. They are prepared from carboxylic acids with carbonyl diimidazole (CDI). 

While the substituents at the nitrogen atoms influence the steric surroundings of the metal, the electronic interaction is dependent on the substitiuents at C4 and C5 and the type of heterocycle (imidazole, imidazoline, benzimidazole, etc.). 

Famotidine (Pepcid) (Fig. 13.57) is 30 times more active than cimetidine in vitro. The side-chain contains a sulfonylamidine group while the heterocyclic imidazole ring of cimetidine has been replaced with a 2-guanidinothiazole ring. Structure-activity studies gave the following results ... 

Nafimidone is an anticonvulsant drug with an obvious two-group disconnection of this type. The a-chloroketone is simply made by chlorination, and substitution is rapid and efficient even with the weakly basic (Chapter 8) heterocycle imidazole. 

Oxidation with singlet oxygen Oxidative opening of heterocycles Imidazole ring opening... 

This reasoning is supported by the observation that the reaction of 2-nitrofuran with trichloromethyl carbanion proceeds in both 3- and 5-positions, because in this case the base-induced p-elimination of HCl from the intermediate o adducts is a fast process [54]. Also the VNS reactions of nitro derivatives of other 5-membered heterocycles, imidazoles [20, 56] and thiazoles [34], with a variety of a-halogeno carbanions have been shown to proceed efficiently. 

According to the third criterion, quinoxaline is the base component The heterocycle imidazole, which is fused to the base component, is numbered in the usual way the pyridine ring, however, is denoted by 1, 2, and so on, and it is not necessary to mark the double bonds. Pyrido[T,2 l,2]imidazo denotes one ring fusion, imidazo[4,5-b]quinoxaline the... 

This amino acid contains the heterocyclic imidazole ring and possesses a unique chemistry. It is both a weak acid and weak base as well as an excellent nucleophile, and the only amino acid that has a pK which approximates physiological pH (7.35). As such, it can both pick up and dissociate protons within the biological milieu. Further, it may so function simultaneously by picking up a proton on one side of the ring, and donating it to the other. It has the potential of acting as a proton-relay system (detailed in Section 4.4.1). 

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