Amines form imines

Primary and secondary amines also react with epoxides (or in situ produced episulfides )r aziridines)to /J-hydroxyamines (or /J-mercaptoamines or 1,2-diamines). The Michael type iddition of amines to activated C—C double bonds is also a useful synthetic reaction. Rnally unines react readily with. carbonyl compounds to form imines and enamines and with carbo-tylic acid chlorides or esters to give amides which can be reduced to amines with LiAlH (p. Ilf.). All these reactions are often applied in synthesis to produce polycyclic alkaloids with itrogen bridgeheads (J.W. Huffman, 1967) G. Stork, 1963 S.S. Klioze, 1975). 

Many biological processes involve an associa tion between two species in a step prior to some subsequent transformation This asso ciation can take many forms It can be a weak associ ation of the attractive van der Waals type or a stronger interaction such as a hydrogen bond It can be an electrostatic attraction between a positively charged atom of one molecule and a negatively charged atom of another Covalent bond formation between two species of complementary chemical re activity represents an extreme kind of association It often occurs in biological processes in which aide hydes or ketones react with amines via imine inter mediates... 

Reactions with Amines and Amides. Hydroxybenzaldehydes undergo the normal reactions with aUphatic and aromatic primary amines to form imines and Schiff bases reaction with hydroxylamine gives an oxime, reaction with hydrazines gives hydrazones, and reactions with semicarbazide give semicarbazones. The reaction of 4-hydroxybenzaldehyde with hydroxylamine hydrochloride is a convenient method for the preparation of 4-cyanophenol (52,53). 

Secondary amines cannot form imines, and dehydration proceeds to give carbon-carbon double bonds bearing amino substituents (enamines). Enamines were mentioned in Chapter 7 as examples of nucleophilic carbon species, and their synthetic utility is discussed in Chapter 1 of Part B. The equilibrium for the reaction between secondary amines and carbonyl compounds ordinarily lies far to the left in aqueous solution, but the reaction can be driven forward by dehydration methods. 

Formation of C—Nu The second mode of nucleophilic addition, which often occurs with amine nucleophiles, involves elimination of oxygen and formation of a C=Nu bond. For example, aldehydes and ketones react with primary amines, RNH2, to form imines, R2C=NR. These reactions proceed through exactly the same kind of tetrahedral intermediate as that formed during hydride reduction and Grignard reaction, but the initially formed alkoxide ion is not isolated. Instead, it is protonated and then loses water to form an imine, as shown in Figure 3. 

The reaction of ketenes (usually formed from treatment of acid chlorides with tertiary amines) with imines is a classic way to form /J-lactams [17,18]. Although widely used, it suffers limitations in scope and efficiency, since free ketenes are... 

One of the potentially most useful aspects of the imine anions is that they can be prepared from enantiomerically pure amines. When imines derived from chiral amines are alkylated, the new carbon-carbon bond is formed with a bias for one of the two possible stereochemical configurations. Hydrolysis of the imine then leads to enantiomerically enriched ketone. Table 1.4 lists some examples that have been reported.118... 

N-donor ligands for Tc(V) and Re(V) are amines, amides, imines and oximes and combinations of these groups. Among these various groups significant differences exist in their ability to form stable complexes, and in the nature of these complexes, mainly because of the different basicity of the groups. 

Reddy et al29 studied the molecule N6,N6-dimethyl-2,6-diaminobenz[cd]-indole, which is shown in Figure 6. The aim was to assess its suitability as an inhibitor of thymidylate synthase, an enzyme which is important in DNA biosynthesis. Three structures were investigated N1H, which is the amine form depicted, and N2H, the imine form, in anti- and syn-conformations, i.e. with the proton on Ni away from or towards the N2 proton, respectively. In the gas phase it was found that the order of stability is N1H > anti-N2H > syn-N2H, in a ratio of 73.1 20.3 6.6. Solvation then further favours the N1H form, and the ratios in solution are calculated to be 98.5 0.5 1.0. Unfortunately, the syn-N2H form is likely to be the conformation that binds most strongly to the enzyme, and so the calculations indicate that this molecule is unlikely to be a suitable inhibitor. 

The reductive alkylation of amines is called the Leuckart-Wallach reaction [112-115]. The primary or secondary amine reacts with the ketone or aldehyde. The formed imine is then reduced with formic acid as hydrogen donor (Scheme 20.27). When amines are reductively methylated with formaldehyde and formic acid, the process is termed the Eschweiler-Clarke procedure [116, 117]. 

Organic dye nanoparticles of DHIA and DHBIA (the chemical structures are shown in Fig. 1) have been synthesized in THF/water mixed solvent by a reprecipitation method [32]. These dye molecules possess a 2-(2-hydroxyphenyl) benzothiazole (HBT) unit, which is known to be more stable as an enol imine form in the ground state and as a keto amine form in the excited state [32, 33] (Fig. 6). The nanoparticles exhibited the AIEE phenomenon mainly due to a restricted intramolecular motion, that is, impediment to free rotation of two end-substituted HBT units around single bonds. It is interesting to note that the... 

Secondary amines react with aldehydes and ketones via addition reactions, but instead of forming imines, produce compounds known as enamines. Initially, there is the same type of nucleophilic attack of the amine onto the carbonyl system, followed by acid-catalysed dehydration but, since the amine is secondary, the product of dehydration is an iminium... 

The reaction is exactly analogous to the chemical aldol reaction (also shown), but it utilizes an enamine as the nucleophile, and it can thus be achieved under typical enzymic conditions, i.e. around neutrality and at room temperature. There is one subtle difference though, in that the enzyme produces an enamine from a primary amine. We have indicated that enamine formation is a property of secondary amines, whereas primary amines react with aldehydes and ketones to form imines (see Section 7.7.1). Thus, a further property of the enzyme is to help stabilize the enamine tautomer relative to the imine. 

Primary amines add to aldehydes and ketones to form imines, R-N=CR2-Secondciry cimines react to form enamines, R 2C=CR(NR2). Hydroxylamine reacts to form an oxime, R2C=NOH. Hydrazine reacts to form a hydrazone,... 

It is synthesized by the reaction of 3,4-dimethoxyphenyl-2-amine and l-(4-methoxyphenyl)-3-butanone with a simultaneous reduction of formed imine, giving the product (11.1.30), the methoxyl-protecting groups of which are cleaved by hydrogen bromide, giving dobutamine (11.1.31) [32,33]. 

Glycoproteins, such as horseradish peroxidase, are coupled selectively to other proteins or NH2-groups bearing molecules via oligosaccharide side chain oxidation. The vicinal OH groups of oligosaccharide residues are oxidized by periodate to aldehyde groups, which react with amines to form imines (Schiff bases). 

The same products are also formed from the reaction of 24 with secondary amines <2004RCB846>. Support for the proposed mechanism is provided by the observation that the same products are obtained when 23 is treated with a pre-formed imine, and by the isolation of the stable enamine 31 in 15% yield as a side product from the reaction of triethylamine with 24. 

Aliphatic ketones react more slowly than aldehydes with amines to form imines (see Table VII). Higher reaction temperatures, longer reaction times, and the removal of water aid in giving high yields of imines (80-95 %). Steric-ally hindered ketones react slowly. Methyl ketones require mild acid catalyst and are more prone to aldol condensation by-products than are methylene ketones [3]. 

Aliphatic and aromatic aldehydes condense with aliphatic and aromatic primary amines to form JV-substituted imines. The reaction is catalyzed by acids and is generally carried out by refluxing the amine and the carbonyl compound with an azeotroping agent in order to separate the water formed. The aliphatic imines (C5-C10) are obtained in good yield but are unstable and must be used directly after their distillation [2b], Tertiary aliphatic and aromatic aldehydes at room temperature react readily and nearly quantitatively with amines to give the imines without the aid of catalysts [la]. Primary aliphatic aldehydes tend to give polymeric materials with amines as a result of the ease of their aldol condensation [3]. The use of low temperatures and potassium hydroxide favors the formation of the imine product [4a, b]. Secondary aliphatic aldehydes readily form imines with amines with little or no side reactions [5]. 

N-oxidation. The oxidation of nitrogen in tertiary amines, amides, imines, hydrazines, and heterocyclic rings may be catalyzed by microsomal enzymes or by other enzymes (see below). Thus the oxidation of trimethylamine to anN-oxide (Fig. 4.19) is catalyzed by the microsomal FAD-containing mono oxygenase. The N-oxide so formed may undergo enzyme-catalyzed decomposition to a secondary amine and aldehyde. This N to C transoxygenation is mediated by cytochromes P-450. The N-oxidation of 3-methylpyridine, however, is catalyzed by cytochromes P-450. This reaction may be involved in the toxicity of the analogue,... 

Gatlin and Davis61 proposed that whereas cytidine existed in the amine form 2, 2 -deoxycytidine was the imine 6. This interpretation however, is incorrect48,49,63 because they did not measure cytidine or... 

However Morita and Nagakura104 concluded from similar studies that in aqueous solution cytosine exists as an equilibrium mixture of two forms, 2 and 6, only. According to these authors the first form predominates in trimethyl phosphate and water at room temperature, but the second prevails at high temperature. The imine form is considered to predominate also in acetonitrile. From the temperature dependence of the absorption spectrum of cytosine in aqueous solution, Morita and Nagakura estimated the tautomeric ratios Kf-e to be equal to 33, 14, and 8 at 30, 50, and 70°, respectively. The energy115 and entropy differences between the imine form 6 and the amine form 2 were evaluated as 5.5 kcal/mole and 12 cal/mole. deg., respectively. 

The physicochemical properties of azacytosines, and the corresponding azacytidines and their derivatives have been studied.116-123 It was shown by IR, NMR, and UV spectroscopy116-118,123 that 6-azacytosine, iV,IV-dimethyl-6-azacytosine, and their 1-methyl derivatives as well as 6-azacytidine, possess the lactam-amine form 14, like cytosine itself. Similar studies118 have shown that 3-methyl-6-azacytosine possesses the lactam-imine form 6, in contrast to 3-methylcytosine, which has the lactam-amine form 3.102... 

Experimental evidence122 shows that 5-azacytosine and 5-azacytidine exist in the lactam-amine form, type 13. Unfortunately, the tautomeric properties of 3-methyl-5-azacytosine have not been studies, so it is difficult to decide whether 5-aza-substitution in 3-methylcytosine causes a tautomeric shift toward the imine form. 

A comparison of the tautomeric constants in the series of N4-substituted cytosines indicates an interesting trend. As seen above, in the case of cytosine itself, the ratio of the tautomers of the amine type 2 to those of the imine type 6 is about 105. In the case of jV4-amino-cytosine134 the amine form 22 predominates by a factor of about 30, while N4-hydroxy compounds have mainly the imine form 21 with tautomeric constant 10 [i.e., Kt (amine/imine) = — 10 1]. Another study136 of this constant gave the value of 25 [Kt (amine/imine) = 4 x 10-2] in favor of the imine. 

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