Amines through nucleophilic substitution

Summary Phosfdiazene bases represent a new class of highly active non-ionic catalysts that rapidly polymerize cyclosiloxanes with equilibrium attained in very short reaction times at very low catalyst levels. To date, phosphazene base catalysts have been considered an academic curiosity because of the complicated and hazardous synthetic protocol used to prepare them. A facile synthetic process has been developed, which yields ionic phosphazene bases in three steps with an overall yield of qrproximately 75%. This is achieved through nucleophilic substitution of ionic phosphonitrilic chloride oligomers with secondary amines, followed by anion exchange. These ionic phosphazenes were found to exhibit similar reactivity in the ring-opening polymerization of cyclosiloxanes to that of the non-ionic phosphazene base. 

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... 

A variation of this method led to the generation of bis-benzimidazoles [81, 82], The versatile immobilized ortho-phenylenediamine template was prepared as described above in several microwave-mediated steps. Additional N-acylation exclusively at the primary aromatic amine moiety was achieved utilizing the initially used 4-fluoro-3-nitrobenzoic acid at room temperature (Scheme 7.72). Various amines were used to introduce diversity through nucleophilic aromatic substitution. Cyclization to the polymer-bound benzimidazole was achieved by refluxing for several hours in a mixture of trifluoroacetic acid and chloroform. Individual steps at ambient temperature for selective reduction, cyclization with several aldehydes, and final detachment from the polymer support were necessary in order to obtain the desired bis-benzimidazoles. A set of 13 examples was prepared in high yields and good purities [81]. 

According to the available experimental data, it is impossible to distinguish between these mechanisms, but the second mechanism seems to be preferred [Scheme (7)] for, according to this Scheme, the reaction of amine addition proceeding through a cyclic transition state is completed in one step, whereas for the reaction to occur according to Scheme (2) or (6) it is additionally necessary to transfer the proton. Then, it is probable that the different mechanisms [Schemes (3) and (5)] may precede formation of one and the same transition state [Scheme (7)]. Note finally that the mechanism of bifunctional catalysis [Scheme (7)] is extremely popular in different reactions of nucleophilic substitution at the saturated carbon atom and reactions with participation of a carbonyl group32>. 

During a study of dihydrocoumarins (68JOC1202) it was observed that 4-(2-bromoethyl)-3,4-dihydrocoumarin (291) was converted into a 4-substituted chroman on reaction with an amine. Ring opening occurs through nucleophilic attack at C-2 and this is followed by an intramolecular nucleophilic substitution. In a similar manner, chroman-4-ylacetic acid results on reaction with potassium hydroxide in methanol. 

In the context of mechanistic studies, the electrochemical behavior and reactions with nucleophiles of 4-chloro-2,6-diphenylpyrylium and 4-chloro(bromo)flavylium have been studied <1999CHE653>. The proposed mechanism for nucleophilic substitution in halogen-substituted pyrylium and flavylium salts passes through formation of a charge-transfer complex that is converted into an ion-radical pair by simple electron transfer. Heterocyclic cleavage of the C-halogen bond occurs at the stage of the radical or the adduct from the reaction of the pyrylium salt and the nucleophile. In this study, an amine nucleophile was used however, the data are likely relevant for other types of nucleophiles as well (Scheme 5). 

Such substitutions using lithium amides, secondary and in some cases tertiary amines as nucleophiles, have been introduced in early sixties as the first expedient method for this unique class of compounds. It is relevant that / ,/ -difluoro- and chlorofluorole-fins readily available through modified Wittig reaction from aldehydes constitute also good ynamine precursors. In the past decade, however, the more versatile lithium aminoacetylide method has gained more prominence. Substitution reactions are still used, among others, for phenyl, tert.-butyl, cinnamyl and cyclopropyl ynamines. 

Imidoyl isothiocyanates 74 are readily available through stepwise nucleophilic substitution of iV-phenyl(phenyl-imino)methylchloromethanimidoyl chloride with secondary amines and potassium thiocyanate. Subsequent thermal intramolecular cyclization of intermediates 74 affords substituted 1,3,5-benzotriazocine derivatives 75 (Equation 8 <2005ARK96>). 

This moleeule interacts in a very stable way in aqueous solution through the aromatie rings with the basal plane of graphite via rr-staeking with the sidewalls of SWCNTs. The succinimidyl residues are highly reactive to nucleophilic substitution by primary and seconday amines of proteins or other moleeules. SWCNTs were incubated in a pyrenebutanoie aeid, sueeinimidyl ester solution (6 mM in DMF or 1 mM in methanol) for 1 h at room temperature followed by careful rinsing in pure DMF or methanol. The proteins were then immobilized by... 

The corresponding ferrilactams (156), which have also been the subject of much attention, are available by the nucleophilic substitution of (155) by amines in the presence of a Lewis acid, usually ZnCb. The substitution occurs with allylic transposition,that is, attack at C-3 of (155). In selected cases, compounds of the type (156) have been prepared by oxidative addition of vinylaziridines or m-4-amino-l-butenols with (2). A bridged ferrilactam bonded through C-2 of the allyl (157) unit has been reported recently and was prepared by way of oxidative addition of a cyclic allylic... 

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