Stable Imine Derivatives

Some compounds in which a nitrogen atom bonds direcdy to electronegative groups with lone pair electrons form stable mine derivatives. These compounds include hydroxylamine, hydrazine, and substituted amine such as semicarbazide and 2,4-dinitrophenylhydrazine. 

Many liquid carbonyl compounds react with these compounds to give sohd derivatives. For example, cyclohexanone reacts with hydroxylamine to give a solid oxime. 

The reaction of carbonyl compounds with semicarbazide yields semicarbazones. The reaction occurs at only one of the two possible NH2 groups. The lone-pair electrons of the NH2 group bonded to the carbonyl are less nucleophilic than those of the other NH2 group because the carbonyl carbon atom decreases the electron density at that nitrogen atom. 

An aldehyde reacts with 2,4-dinitrophenylhydrazine to give a bright, yellow-to-orange crystalline solid called a 2,4-dinitrophenylhydrazone (2,4-DNP). 

Two equivalents of benzaldehyde react with hydrazine to give a compound with molecular formula C14H12 2- Draw the structure of the compound. 

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Under conditions similar to those already outlined, stable aziridin imine derivatives, e.g. (422) and (423), can be prepared in excellent yields (70-80%) by treating the appropriate a-bromoamidines (easily accessible from the amide precursor) with potassium t-butoxide in ether <70AG(E)38l). At low temperatures the elimination proceeds with high regio- and stereo-selectivity at -40 °C (421) yields predominantly (422). 

As the last point in Sect. IV, we discuss briefly the reactions of chiral sulfur compounds with electrophilic reagents. In contrast to nucleophilic substitution reactions, the number of known electrophilic reactions at sulfur is very small and practically limited to chiral tricoordinate sulfur compounds that on reacting with electrophilic reagents produce more stable tetracoordinate derivatives. It is generally assumed that the electrophilic attack is directed on the lone electron pair on sulfur and that the reaction is accompanied by retention of configuration. As typical examples of electrophilic reactions at tricoordinate sulfur, we mention oxidation, imination, alkylation, and halogenation. All these reactions were touched on in the section dealing with the synthesis of chiral tetracoordinate sulfur compounds. 

In general, imine derivatives are configurationally stable at room temperature and form Z- and E-isomers which can be easily differentiated by various NMR methods. 

Imines derived from macrocyclic ketones (C10 to C 15 ) and (- )-(S)-a-(methoxymcthyl)benzene-ethanamine are successfully deprotonated using LDA ( —25 JC. THF. 1 h)9. In contrast to azaenolates of C0- to C8-membered cyclic ketones, which show only E geometry, Z-isomers are observed with macrocyclic imines. As evident from H-NMR data, azaenolates of cyclodecanone imines generated under these conditions are a mixture of E- and Z-isomers (33 66), whereas azaenolates of cyclododecanone and cyclopenladecanone imines arc formed as the pure. E-isomers (see Table 3). Upon heating the solutions of metalated imines to reflux for 1 hour, complete isomerization to the thermodynamically more stable Z-isomers occurs. 

However, these compounds are generally unstable. Most imines with a hydrogen on the nitrogen spontaneously polymerize.143 Stable hemiaminals can be prepared from polychlorinated and polyfluorinated aldehydes and ketones, and diaryl ketones do give stable imines Ar2C=NH.144 Aside from these, when stable compounds are prepared in this reaction, they are the result of combinations and condensations of one or more molecules of 12 and/or 13 with each other or with additional molecules of ammonia or carbonyl compound. The most important example of such a product is hexamethylenetetramine145 (11), prepared from ammonia and formaldehyde.146 Aromatic aldehydes give hydrobenzamides ArCH(N=CHAr)2 derived from three molecules of aldehyde and two of ammonia.147... 

The second type of weak bases for imine ligations are 1,2- or 1,3-heterosubstituted amines of amino thiols and amino alcohols. Of the two, the amino thiols appear to be the more suitable choice because they form stable thiazolidine derivatives under very mild reaction condi-tions 84"89,114 121 140 Furthermore, the 1,2-and 1,3-aminothiol moieties are found in cysteines and homocysteines that form a stable heterocyclic ring with an aldehyde within ten minutes at pH 4-5. Thiazolidine ring formation has been successfully used to ligate both linear and constrained peptides to K2K dendron types of cores and proteins containing a-oxoacyl groups. 

The oxidation of imines derived from substituted cyclohexanones occurs predominantly from the equatorial direction. However, the product oxaziridines can undergo subsequent equilibration to favor a more stable conformation which places the bulkier nitrogen substituent in an equatorial conformation (equation 44)219. 

Quaternization (see Section 6.09.5.3) significantly increases the stability of the 1,2,3,4-thiatriazole ring. Moreover, many mesoionic and imine derivatives are quite stable in comparison with the parent compounds. 

In this context, it is worthwhile to note that the use of alcohols in catalytic hydrogenations may lead to related aldehydes or ketones which in turn are capable of producing stable imidazolid-4-one derivatives with the N-terminal amine group.Moreover, when carrying out hydrogenations in an alcohol, oxygen has to be removed meticulously from the system to avoid as a serious side reaction N-alkylation via aldehyde and related imine derivatives which has been observed to occur readily, particularly with methanol as the solvent.f l An additional inconvenience observed when air is not rigorously excluded, is the formation of palladium complexes with the peptides. 

A variety of reagents have been described for reductive amination, a labelhng reaction based on the attachment of an amino group at the carbonyl group in a reducing sugar under mild acidic conditions. This yields an acid-labile Schiff base (imine derivative), which is subsequently reduced to a stable secondary amine. Frequently applied reagents are 2-aminopyridine (PA), 2-aminoacridone (2-AMAC), and 4-aminobenzene derivatives such as 4-aminobenzoic ethyl ester (ABEE) or aminobenzoic butyl ester (ABBE). 

Conversely, Hosomi and Sakurai have shown that deprotonation with alkyllithium reagents occurs predominantly at the more substituted side of the cyclohexylimine of 2-methylcyclohexanone (equation 41). However, the low yield in this sequence (as compared with, for example, equations 39 and 40) places this route to 2,2-disubstituted systems only equal with other techniques such as those that employ the more stable enolate-derived 2-alkyl cyclic ketones. Further, in no case did deprotonation of an unsymmetrical, acyclic ketone imine with an alkyllithium result in synthetically usable selectivity for the more substituted carbon. 

This class of compound is called the imines, and usually they are not very stable. However, if one of the substituents on the carbon is an aryl group then they become quite stable. Imines are also known as Schiff bases. For all of these derivatives, the original nitrogen compound possessed at least two hydrogen atoms, so that the nitrogen could end up doubly bonded to what was the carbonyl carbon. In contrast, if a secondary amine, NHR2, is used, suggest what would be the product in this case. 

Oxatriazolium-5-aminides (9) are structurally related to sydnon-imines (3). As with sydnonimines, the 5-imine derivatives are stable only as salts or in their N-acylated forms. 3-Cyclohexyl-1,2,3,4-oxatriazole-5-imine hydrochloride was first synthesized by Finnegan and Henry in 1965 [55]. The biological activity was reported by Masuda et al. in 1971 [56]. Oxatriazole-5-imines (9) have been reported to be an important class of NO donors and potent antiplatelet, fibrinolytic, thrombolytic, and bronchiectatic agents [57]. However, an extensive investigation of the NO-releasing and other biologi-... 

Soon after, the groups of Ricci [35] and Schaus [36] also employed a-amidosulfones as stable imine precursors in cinchona-catalyzed Mannich reactions. Ricci and coworkers reported [35] that, under PTC conditions (toluene/aqueous K2C03) using 75 as a catalyst (1 mol%), both the aliphatic and aromatic a-amido p-tolylsulfones 76 reacted with the malonates to afford the Mannich adducts 77 with high levels of enantioselectivity (85-99% ee) (Scheme 8.25). The subsequent decarboxylation/ transesterification of 77 gave the corresponding [3-amino acid derivatives without any alternation of the optical purities. The chiral dihydropyrimidones 80 were also successfully synthesized by Schaus and coworkers via the cinchonine catalyzed... 

Conversion to other carbonyl compounds is more tricky because of the increased likelihood of enolisation. The protected cyanohydrins 136 can be reduced to the aldehydes 135 with 1.5 equivalents of DIBAL and cautious acidification. The more stable ketones 138 are best made in two stages.41 Additions of Grignard reagents gives the imine derivatives 137 that can be worked up in acid to give the ketones 133. 

The reactions of indole with Ae imines derived from acetaldehyde and r-butylamine and isopropylamine have been reported using acetic acid as the proton source in benzene. A poor yield (15%) is obtained with ethylidene-t-butylamine but a better yield (60%) results with the isopropylamine analog (equation 44). A one pot reaction using indole, acetaldehyde and isopropylamine gives the same product in 40% yield. This type of reaction depends for its success on the stability of the aldimine under the acidic reaction conditions. However, while the more sterically demanding primary amines afford the most stable imines, it appears that this can lead to too great a steric demand in the transition state leading to reaction with, for example, indole, and hence the low yield reported in the f-butylamine reaction. 

Stable imines. Imines derived from aliphatic amines usually have the tendency to isomerize to the enamine form. However, the bissilylated methylimines are stable therefore, they are potentially useful synthetic intermediates. 

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