Heterocyclic-activated displacement

Poly(arylene ether triazole)s have also been prepared by heterocyclic-activated displacement polymerization [36], The 1,2,4-triazole unit sufficiently activated, albeit weakly, aryl fluorides for nucleophilic displacement. Several 3,5-bis(4-fluorophenyl)-4-aryl-l,2,4-triazoles were polymerized with various bis-phenols to yield polymers with Tgs from 185 to 230 °C [36]. The 1,2,4-triazole unit appears to be one of the more weakly activating heterocycles towards nucleophilic substitution polymerization. 

Acylation of benzamidoxlme (144) with chloropropionyl chloride gives the 0-acylated derivative (145). Reaction of that intermediate with diethylamine serves first to cyclize the molecule to the 1,2,4-oxadiazole heterocycle subsequent displacement of the halogen on the side chain gives oxolamine (146),a drug with antltussive and spasmolytic activity. 

Synthesis of all these heterocycle activated polyethers is carried out in polar aprotic solvents, such as NMPs, by the K2CO3 method. The effective displacement reactions are reported at varied temperatures (140-190°C) and durations (3-24 h). 

Another very mild procedure involves reaction of the alcohol with the heterocyclic 2-chloro-3-ethylbenzoxazolium cation.28 The alcohol adds to the electrophilic heterocyclic ring, displacing chloride. The alkoxy group is thereby activated toward a nucleophilic substitution that forms a stable product, 3-ethylbenzoxazolinone. 

The addition of allylmagnesium halides (2 equiv.) to 1,3-azadienes affords after in situ alkylation dihomoallylamines, which are useful intermediates in the synthesis of azepines or related heterocycles. Activation of the C=N moiety of aldimines by 1-benzotriazolyltrimethylsilane minimizes side reactions. The mechanism involves reversible addition of BtTMS (216) to the imine 217 followed by displacement of the benzotriazolyl group by a Grignard reagent (equation 148). ... 

A few studies on solvolyses by alcohols and by water are available. The hydrolyses studied include displacement of alkylamino groups from acridine antimalarials and of halogen from other systems. In all cases, these reactions appeared to be first-order in the heterocyclic substrate. By a detailed examination of the acid hydrolysis of 2-halogeno-5-nitropyridine, Reinheimer et al. have shown that the reaction rate varies as the fourth power of the activity of water, providing direct evidence that the only reactive nucleophile is neutral water, as expected. 

A heterocyclic ring may be used in place of one of the benzene rings without loss of biologic activity. The first step in the synthesis of such an agent starts by Friedel-Crafts-like acylation rather than displacement. Thus, reaction of sulfenyl chloride, 222, with 2-aminothiazole (223) in the presence of acetic anhydride affords the sulfide, 224. The amine is then protected as the amide (225). Oxidation with hydrogen peroxide leads to the corresponding sulfone (226) hydrolysis followed by reduction of the nitro group then affords thiazosulfone (227). ... 

Hydrazinopyridazines such as hydralazine have a venerable history as anti hypertensive agents. It is of note that this biological activity is maintained in the face of major modifications in the heterocyclic nucleus. The key intermediate keto ester in principle can be obtained by alkylation of the anion of pi peri done 44 with ethyl bromo-acetate. The cyclic acylhydrazone formed on reaction with hydrazine (46) is then oxidized to give the aromatized compound 47. The hydroxyl group is then transformed to chloro by treatment with phosphorus oxychloride (48). Displacement of halogen with hydrazine leads to the formation of endralazine (49). ... 

The finding that the anthelmintic thiazoloimidazole levamisole showed immunoregulatory activity spurred further investigation of this heterocyclic system. Synthesis of a highly modified analogue starts by displacement of bromine in keto ester 149 by sulfur in substituted benzimidazole 148. Cyclization of the product (150), leads initially to the carbinol 151. Removal of the ester group by saponification in base followed by acid-catalyzed dehydration of the carbinol affords the immune regulator tilomisole (152) [28]. 

The common characteristics of the above mentioned heterocycles are electron withdrawing and a site of unsaturation that can stabilize the negative charge developed by the displacement reaction through resonance. For example, the thiazole activated halo displacement is similar to that of a conventional activating group as shown in Scheme 1. The activation is derived from the electron affinity and the stabilization of the negative... 

Figure 27 shows plots of all the available EM s for closures of small- and common-sized saturated carbocycles and heterocycles by intramolecular nucleophilic displacement. Clearly, a-values as small as 0.1 would be required in order to calculate extrathermodynamically from (67) EM-values comparable to those actually observed for ring-sizes 3 and 4, and an even smaller value would be necessary for ring-size 5. This would lead to the conclusion that the effect of ring strain on cyclisation rates is insignificant. The same conclusion was recently drawn by Benedetti and Stirling (1983), based on rates and activation parameters for the cyclisation of bis-sulphonyl-stabilised carbanions to 3-, 4-, and 5-membered bis-sulphonylcyloalkanes. 

The second salient feature of heterocycles is the marked activation at positions a- and y- to the heteroatom. For N-containing heterocycles, the presence of the N-atom polarizes the aromatic ring, thereby activating the a and y positions, making them more prone to nucleophilic attack. The order of SNAr displacement of heteroaryl halides with EtO is [14] ... 

---