Amine by nucleophilic substitution

Reactions of 5f/-2-methyl-l,2,4-triazepino[2,3- ]benzimidazol-4-one 71, prepared by reaction of 1,2-diaminobenz-imidazole 72 with acetoacetic ester 73, with different reagents was described, in the search of new heterocycles with biological activity <2002CHE598>. When lactam 71 was treated with aromatic aldehydes in boiling 1-BuOH with addition of piperidine 74, 577-3-arylidene-2-methyl-l,2,4-triazepino[2,3- ]benzimidazol-4-ones 75a-c were obtained (Scheme 7). Coupling lactam 71 with phenyldiazonium chloride 76 in dioxane afforded the 3-phenylazo-substituted tricycle 77. When 71 was treated with phosphorus pentasulfide 78 in boiling dioxane or pyridine, its thio analog 79 was obtained. The reaction proceeded most efficiently when lactam 71 was refluxed with twofold excess of 78 in dry dioxane. These thiones 79 react with ammonia and amines by nucleophilic substitution. When 79 was refluxed with ammonia, benzylamine, piperidine, or morpholine, the 4-amino-substituted tricycles 80a-d were obtained. All the described compounds were identified by NMR, mass spectrometry, and IR spectroscopy. 

Because nitriles can be prepared from alkyl halides by nucleophilic substitution with cyanide ion the overall process RX RC=N RCH2NH2 leads to primary amines that have one more carbon atom than the starting alkyl halide... 

Mononitration of a mixture of J- and 4 chlorobenzotnfluondes followed by nucleophilic substitution by hydroxide, ammonia, or a primary or secondary amine in dimethylformamide, leads to 5 chloro 2 nitrobenzotrifluoride The 4-chloro-3-nitro isomer selectively reacts and can be removed as a water-soluble phenoxide [19] (equation 16)... 

The relatively poor resonance activation of the 2-Le-3-aza orientation in bicyclics (cf. Section IV, A) is illustrated by nucleophilic substitutions below. Vigorous conditions are required for methoxylation (110°, 17 hr, quantitative yield) of 3-bromocinnoline and for amination (aqueous ammonia, copper sulfate, 20 hr, high yield) of 3-bromo- (at 130°) or of 3-chloro-derivatives (at 165°). 3,4-Dichlorocinnoline gives predominantly 4-substitution in hydra-zination (90% yield, 20°, 4 days in alcohol), amination (70% yield, 150°, 22 hr in alcohol), and hydroxylation (50% yield, 150°, 22 hr, aqueous ammonia). The poorer-leaving phenoxy group in 3-chloro-4-phenoxycinnoline, is displaced with ammonium acetate (160°, few mins, 60% yield). ... 

One of the most important reactions of purines is the bromination of guanine or adenine at the C-8 position. It is this site that is the most common point of modification for bioconjugate techniques using purine bases (Figure 1.53). Either an aqueous solution of bromine or the compound N-bromosuccinimide can be used for this reaction. The brominated derivatives then can be used to couple amine-containing compounds to the pyrimidine ring structure by nucleophilic substitution (Chapter 27, Section 2.1). 

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>. 

By heating an alkyl halide with an alcoholic solution of ammonia in a sealed tube, a mixture of amines is formed by nucleophilic substitution reaction. 

As synthetic steps, the Michael additions of nitrogen nucleophiles were followed by nucleophilic substitutions of the chlorine atom with a primary amine and, finally, alkylations of the then secondary amino group with various alkyl bromides were performed just as previously developed for the chloro ester 1-Me in solution (see, e.g. Schemes 25,27,36 etc.). With differently substituted pyra-zoles as Michael addends, different primary amines and alkyl bromides, combinatorial libraries consisting of 8, 24 and 84 compounds were thus successfully prepared in ca. 60% yield and proved by the LC-MS technique to contain all the individual compounds in about equal amounts (Scheme 80) [127]. 

The mechanism for the reactions with phosphorus halides can be illustrated using phosphorus tribromide. Initial reaction between the alcohol and phosphorus tribromide leads to a trialkyl phosphite ester by successive displacements of bromide. The reaction stops at this stage if it is run in the presence of an amine which neutralizes the hydrogen bromide that is formed.9 If the hydrogen bromide is not neutralized the phosphite ester is protonated and each alkyl group is successively converted to the halide by nucleophilic substitution by bromide ion. The driving force for cleavage of the C—O bond is the... 

The divergent method is illustrated in Fig. 2-22 for the synthesis of polyamidoamine (PAMAM) dendrimers [Tomalia et al., 1990]. A repetitive sequence of two reactions are used—the Michael addition of an amine to an a,P-unsaturated ester followed by nucleophilic substitution of ester by amine. Ammonia is the starting core molecule. The first step involves reaction of ammonia with excess methyl acrylate (MA) to form LXIII followed by reaction with excess ethylenediamine (EDA) to yield LXIV. LXV is a schematic representation of the dendrimer formed after four more repetitive sequences of MA and EDA. 

Studenov and Beriidge introduced a series of potential F-labeled extractable MBF tracers in the year 2001 that were accessible via reliable 1-2-step radiosynthesis sequences. Five F-labeled amines and four quaternary ammonium salts were obtained by nucleophilic substitution either at aliphatic precursors or at aromatic compounds [71]. Figure 10 summarizes the synthesis of mentioned compounds. 

Although there have been few new developments in the period since 1993, halogenopyrazines 42 have been convenient precursors for a variety of pyrazine derivatives. For example, the halogenopyrazines 42 are cyanated by palladium-catalyzed cross-coupling with alkali cyanide or by treatment with copper cyanide in refluxing picoline, to yield cyanopyrazines 48. Alkoxypyrazines 49 are produced by treatment with alkoxide-alcohol, and aminopyrazines 50 are prepared by amination with ammonia or appropriate amines. The nucleophilic substitution of chloropyrazine with sodium alkoxide, phenoxide, alkyl- or arylthiolate is efficiently effected under focused microwave irradiation <2002T887>. 

The mechanism of the thermal ROP of (Cl2PN)3 has been proposed to involve a cationic mechanism (see Scheme 8.2 in Section 8.1.2.2). The unique reaction sequence involving ROP followed by nucleophilic substitution with oxygen- or nitrogen-based nucleophiles (generally alkoxides, aryloxides or primary amines) permits a diverse range of polyorganophosphazenes to be... 

The first step in the submonomer method involves the acylation of a halogenated acetic acid on the resin under standard conditions. In the second step the side chain of the peptoid is introduced by nucleophilic substitution of the halide with an excess of the primary amine. 

Illustrative examples of cleavage reactions of /V-arylbenzylaminc derivatives are listed in Table 3.25. Aromatic amines can be immobilized as /V-bcnzylanilincs by reductive amination of resin-bound aldehydes or by nucleophilic substitution of resin-bound benzyl halides (Chapter 10). The attachment of the amino group of 5-aminoin-doles to 2-chlorotrityl chloride resin has been reported [486]. Anilines have also been linked to resin-bound dihydropyran as aminals [487]. 

Aminative replacement in compounds other than those bearing halogen atoms are uncommon, but 6-aminophenanthridine is easily prepared by heating 6-phenoxyphenanthridine with urea296 and 6-anilinophenanthridine has been obtained by the action of aniline on the 6-phenoxy compound.268 The formation of 6-anilinophenanthridine from phenanthridine iV-oxide and phenyl isocyanate probably proceeds via an initial 1,3-dipolar addition, followed by nucleophilic substitution and decarboxylation (Scheme 4).309... 

Amides can be prepared from acid chloride by nucleophilic substitution. When ammonia is treated with acid chlorides it gives a primary amide. Acid chloride on treatment with a primary amine gives a secondary amide, and on treatment with a secondary amine gives a tertiary amide. Tertiary amines cannot be used on this reaction because they do not form a stable product. 

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