Nucleophilic substitution 3 + 2 cyclization

This problem covers a reaction sequence and a variety of different reactions, some easier than others. This one includes enolate anions, electrophilic cyclization, nucleophilic substitution, and simple carboxylic acid chemistry. 

Arylamino-2-chloroprop-2- enoic esters (72) obtained from 2-chloroaceto acetic ester (71) and arylamines, react with thiourea to yidd substituted 2-aminothiazoles (73), probably by initial nucleophilic substitution of the chloro atom of 72, followed by cyclization with loss of aniline (Scheme 33) (729). 

Intramolecular nucleophilic displacement of the bromo group by an azine-nitrogen occurs in the cyclization of A-2-quinaldyl-2-bromo-pyridinium bromide (248) to give the naphthoimidazopyridinium ring system. The reaction of 2-bromopyridine and pyridine 1-oxide yields l-(2-pyridoxy)pyridinium bromide (249) which readily undergoes an intramolecular nucleophilic substitution in which departure of hydrogen as a proton presumably facilitates the formation of 250 by loss of the JV-oxypyridyl moiety. 

The cyclization pathway proposed (81UK1252) involves nucleophilic substitution of the hetero group (XR) by the formamide amino group to form either enyne formamide 157 or imine 158. 

Highly electron-deficient 1,3,6-trinitrobenzene (145) treated with phenyl acet-amidines 146 in ethanol provided low yields of a dinitroindole derivatives, probably 4,6-dinitroindoles 148 (77JOC435). Formation of indole derivatives 148 can be explained by nucleophilic substitution of the activated aromatic hydrogen leading to intermediates 147, which then cyclized to the final products 148 (Scheme 22). 

Pyridino-oxazoles 198 were obtained in an analogous way starting from o-bromoaminopyridine 196, which was first acylated and then cyclized imder microwave irradiation at 165 °C in DMA via an aromatic nucleophilic substitution (Scheme 71) [126]. 

In the case of aromatic amines there is an initial nucleophilic substitution catalyzed by the silanol groups of the silica gel layer to yield arylaminobenzoquinone derivatives, that undergoe oxidative cyclization to the corresponding dioxazines [1]. 

Nucleophilic Substitutions and Cyclizations via Sila-Pummerer Reactions... 

Organic halides play a fundamental role in organic chemistry. These compounds are important precursors for carbocations, carbanions, radicals, and carbenes and thus serve as an important platform for organic functional group transformations. Many classical reactions involve the reactions of organic halides. Examples of these reactions include the nucleophilic substitution reactions, elimination reactions, Grignard-type reactions, various transition-metal catalyzed coupling reactions, carbene-related cyclopropanations reactions, and radical cyclization reactions. All these reactions can be carried out in aqueous media. 

As mentioned earlier, the McDonald group was able to extend their epoxide-domino-cyclization strategy to 1,5,9-triepoxides [10]. Indeed, they were successful in converting precursor 1-143 into the tricyclic product 1-146 in 52 % yield after hydrolysis (Scheme 1.36) [41]. As a possible mechanism of this polyoxacyclization it can be assumed that, after activation of the terminal epoxide by BF3, a sequence of intramolecular nucleophilic substitutions by the other epoxide oxygens takes place, which is induced by a nucleophilic attack of the carbonate oxygen, as indicated in 1-144 to give 1-145. 

Nucleophilic substitution of the chloropyridazine 166 with sodium azide in DMF is followed by cyclization to give the fused tetrazole 167 (Equation 41) <1997JHC39>. 

Nucleophilic substitution of a halogeno-heterocycle is the key step in the synthesis of imidazo-, oxazolo-, thiazolo-, and benzothiazolopyridopyrimidines 255 and 256 <2000T5185> and 257. Intramolecular iV-acylation is the final cyclization step leading to the thiazolino compound 258 (Scheme 63) <1995AF306>. 

A diverse group of organic reactions catalyzed by montmorillonite has been described and some reviews on this subject have been published.19 Examples of those transformations include addition reactions, such as Michael addition of thiols to y./bunsatu rated carbonyl compounds 20 electrophilic aromatic substitutions,19c nucleophilic substitution of alcohols,21 acetal synthesis196 22 and deprotection,23 cyclizations,19b c isomerizations, and rearrangements.196 24... 

Pyrimido[4,5-d]pyridazine-2,5-diones were synthesized in a similar manner, employing several hydrazines (R3 = H, Me, Ph) for the nucleophilic substitution prior to cyclative cleavage. Due to the high nucleophilicity of the hydrazines, reaction times for the substitution step could be reduced to 30 min. In the case of phe-nylhydrazine, concomitant cyclization could not be avoided, which led to very low overall yields of the isolated products. 

A similar but simpler 4-imino-hexahydropyrrolo[l,2-tf]pyrazin-l(277)-one 311 was prepared starting from the product obtained by nucleophilic substitution of a primary amine to the bromoacetamide of the L-prolylnitrile 310 (Scheme 40). The cyclization occurred directly in basic medium by refluxing for 96 h in EtOAc. This compound showed a potent activity as an orally bioavailable dipeptidyl peptidase IV inhibitor with anti-hyperglycemic properties <2003JME2774>. 

The prodrugs examined here undergo a common, two-step mechanism of activation (hence their designation as double prodrugs) first, hydrolysis of the carboxylate group occurs, followed by intramolecular nucleophilic substitution to liberate the active amine (for reviews see [168] [169] [237] [238]). Such reactions of cyclization-elimination are analogous to those discussed in Sect. 8.5.7. 

Fig. 8.22. 2-[(Acyloxy)methyl]benzamides (8.187) as double prodrugs of active amines. Activation is by cyclization-elimination in a two-step sequence, namely hydrolase-catalyzed hydrolysis of the carboxylate moiety followed by an intramolecular nucleophilic substitution with...

This chapter, therefore, ends the monograph with a potpourri of reactions all of which occur without a change in oxidation state. In many cases, the reaction is one of nucleophilic attack at an electrophilic C-atom. The result is often hydrolytic bond cleavage (e.g., in carbohydrate conjugates, disubstitut-ed methylene and methine groups, imines, oximes, isocyanates, and nitriles, and various ring systems) or a nucleophilic substitution (e.g., hydrolytic de-halogenation of halocarbons and chloroplatin derivatives, and cyclization reactions). The formation of multiple bonds by dehydration is a special case to be discussed separately. 

Another type of dehalogenation occurs in xenobiotic metabolism, namely halide elimination with cyclization. These intramolecular nucleophilic substitutions are discussed in Sect. 11.4.2 (nitrogen mustards) and 11.8. 

A large variety of metabolic cyclization reactions, counterparts to the reactions of hydrolytic ring opening discussed above, occur without any change in the degree of oxidation, and often nonenzymatically. Such reactions proceed by various mechanisms of intramolecular nucleophilic substitution, with elimination of amine, phenol, halide, or H20. 

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