Amination reactions nucleophilic substitution

Synthesizing amines with nucleophilic substitution reactions is normally an Sp 2 process. This means that methyl amines react more readily than primary cimines, and secondary and tertiary amines show very little reactivity. 

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. 

The azide ion is a better nucleophile than amines, but it has to be reduced to the amine after nucleophilic substitution. Lithium aluminum hydride (LiAlH4) in ether followed by treatment with water reduces the azide ion to the amine. Figures 13-11 and 13-12 illustrate two examples of this reaction. 

It appears also that, for the synthesis of large libraries, there are few reactions that fulfil these prerequisites. Among the reactions that proved to have wide applicability, amide bond formations and peptide-like protecting group strategies can be found. In a general way all amine functionalization reactions are usually effective and lead to stable structures (i.e. sulfonamide, carbamate, urea, thiourea formation, reductive amination and nucleophilic substitution). Moreover, for any of these reactions the suitable linker can be easily selected from various literature sources. 

Chemical shift The position of an NMR signal, related to molecular structure near the nucleus observed. Chichibabin reaction Nucleophilic substitution of an amine group in pyridine, using sodium amide in liq-... 

Other Nucleophilic Substitution Reactions. Nucleophilic substitution of a variety of substituted aminoiminomethanesulfonic acids with cyanide leads to the corresponding aminoimi-noethanenltrlles in 30-87% yield. A number of substituted aminoiminomethanesulfonic acids react with sodium azide in acetic acid to give the corresponding 5-aminotetrazole. This reaction Is subject to pronounced steric hindrance. Hydroxyl-amine and cyanamlde also give nucleophilic substitution of the sulfonic acid group. ... 

Nucleophilic Reactions.—Nucleophilic substitution in the isothiazole nucleus, as well as a variety of nucleophilic ring fissions, continue to attract a good deal of attention. The methylsulphonyl group is particularly prone to nucleophilic replacement 3,5-bis(methylsulphonyl)isothiazole-4-carbo-nitrile, readily accessible from malononitrile and carbon disulphide, yields the 5-(substituted)amino-compounds on treatment with ammonia, amines, or hydrazine, and the 5-ethoxy-compound when treated with ethanol in the presence of sodium carbonate. The electron-attracting cyano-group appears to promote the nucleophilic displacement, since 3,5-bis(methyIsuIphonyl)-4-phenylisothiazole displays reduced reactivity. ... 

With the exception of the nuclear amination of 4-methylthiazole by sodium amide (341, 346) the main reactions of nucleophiles with thiazole and its simple alkyl or aryl derivatives involve the abstraction of a ring or substituent proton by a strongly basic nucleophile followed by the addition of an electrophile to the intermediate. Nucleophilic substitution of halogens is discussed in Chapter V. 

Amines like ammonia are weak bases They are however the strongest uncharged bases found m significant quantities under physiological conditions Amines are usually the bases involved m biological acid-base reactions they are often the nucleophiles m biological nucleophilic substitutions... 

Nucleophilic substitution occurs in positions a and y to the N-oxide group. In nearly all these reactions deoxygenation occurs giving the substituted heterocychc amine. 

Methyl bromide slowly hydrolyzes in water, forming methanol and hydrobromic acid. The bromine atom of methyl bromide is an excellent leaving group in nucleophilic substitution reactions and is displaced by a variety of nucleophiles. Thus methyl bromide is useful in a variety of methylation reactions, such as the syntheses of ethers, sulfides, esters, and amines. Tertiary amines are methylated by methyl bromide to form quaternary ammonium bromides, some of which are active as microbicides. 

A.mina.tlon. Amination describes the introduction of amino groups into aromatic molecules by reaction of ammonia or an amine with suitably substituted halogeno, hydroxy, or sulfonated derivatives by nucleophilic displacement. Although reaction and operational conditions vary, the process always involves the heating of the appropriate precursor with excess aqueous ammonia or amine under pressure. 

Nucleophilic substitution of the chlorine atom in 2-chloropyrazine and 2-chloroquinoxa-lines has been effected with a variety of nucleophiles, including ammonia and amines, oxygen nucleophiles such as alkoxides, sodium azide, hydrazine, sulfur containing nucleophiles, cyanide, etc., and reactions of this type are typical of the group (see Chapter 2.02). 

Furazano[3,4-d]pyrimidine, 7-amino-synthesis, 6, 729 UV spectra, 6, 713 Furazanopyrimidines amine synthesis from, 5, 591 synthesis, 6, 418 Furazano[3,4-d]pyrimidines nucleophilic attack, 6, 719 nucleophilic substitution, 6, 713 reduction, 6, 402 7-substituted reactions, 6, 722 Furazano[3,4-a]quinolizines synthesis, 6, 730... 

Nucleophilic substitution reactions that occur imder conditions of amine diazotization often have significantly different stereochemisby, as compared with that in halide or sulfonate solvolysis. Diazotization generates an alkyl diazonium ion, which rapidly decomposes to a carbocation, molecular nitrogen, and water ... 

These Br nsted-type plots often seem to be scatter diagrams until the points are collated into groups related by specific structural features. Thus, p-nitrophenyl acetate gives four separate, but parallel, lines for reactions with pyridines, anilines, imidazoles, and oxygen nucleophiles.Figure 7-4 shows such a plot for the reaction of trans-cmmm c anhydride with primary and secondary aliphatic amines to give substituted cinnamamides.All of the primary amines without substituents on the a carbon (R-CHi-NHi) fall on a line of slope 0.62 cyclopentylamine also lies on this line. If this line is characteristic of normal behavior, most of the deviations become qualitatively explicable. The line drawn through the secondary amines (slope 1.98) connects amines with the structure R-CHi-NH-CHi-R. The different steric requirements in the acylation reaction and in the model process... 

In spite of the potential complexity of the general problem, even when restricted to the reagent family of amines, the nucleophilicities of such series as meta- and pom-substituted pyridines and anilines appear to correlate very closely with the expected substituent effects and with the basicities. This has been verified in the following cases (i) The reaction of pyridines (R = H, m- andp-CHs) with 2-chloro-3-nitro-, 2-chloro-5-nitro-, and 4-chloro-3-nitro-pyridines. ... 

Arynes are intermediates in certain reactions of aromatic compounds, especially in some nucleophilic substitution reactions. They are generated by abstraction of atoms or atomic groups from adjacent positions in the nucleus and react as strong electrophiles and as dienophiles in fast addition reactions. An example of a reaction occurring via an aryne is the amination of o-chlorotoluene (1) with potassium amide in liquid ammonia. According to the mechanism given, the intermediate 3-methylbenzyne (2) is first formed and subsequent addition of ammonia to the triple bond yields o-amino-toluene (3) and m-aminotoluene (4). It was found that partial rearrangement of the ortho to the meta isomer actually occurs. 

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