Imines with amines

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]. 

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... 

Polyamines can also be made by reaction of ethylene dichloride with amines (18). Products of this type are sometimes formed as by-products in the manufacture of amines. A third type of polyamine is polyethyleneimine [9002-98-6] which can be made by several routes the most frequently used method is the polymeriza tion of azitidine [151 -56 ] (18,26). The process can be adjusted to vary the amount of branching (see Imines, cyclic). Polyamines are considerably lower in molecular weight compared to acrylamide polymers, and therefore their solution viscosities are much lower. They are sold commercially as viscous solutions containing 1—20% polymer, and also any by-product salts from the polymerization reaction. The charge on polyamines depends on the pH of the medium. They can be quaternized to make their charge independent of pH (18). 

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). 

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. 

Imine formation is reversible. Show all the steps involved in the acid-catalyzed reaction of an imine with water (hydrolysis) to yield an aldehyde or ketone plus primary amine. 

Step 1 of Figure 29.14 Transimination The first step in transamination is trans-imination—the reaction of the PLP—enzyme imine with an a-amino acid to give a PLP—amino acid imine plus expelled enzyme as the leaving group. The reaction occurs by nucleophilic addition of the amino acid -NH2 group to the C=N bond of the PLP imine, much as an amine adds to the C=0 bond of a ketone or aldehyde in a nucleophilic addition reaction (Section 19.8). The pro-tonated diamine intermediate undergoes a proton transfer and expels the lysine amino group in the enzyme to complete the step. 

The palladium(O) complex undergoes first an oxydative addition of the aryl halide. Then a substitution reaction of the halide anion by the amine occurs at the metal. The resulting amino-complex would lose the imine with simultaneous formation of an hydropalladium. A reductive elimination from this 18-electrons complex would give the aromatic hydrocarbon and regenerate at the same time the initial catalyst. 

PreUminary studies on the racemic reaction of protected imines with ni-tromethane showed that the thiourea and the amine mutually weakened their reactivities. However, the bifunctional amino-thiourea led to good results. Enantioselectivity of the adduct depended on the protecting group, P(0)Ph2 affording the best results (76% ee). Then, other aromatic imines substrates were successfully phosphorylated with good to high enantioselec-tivities (63-76% ee). 

The direct reductive amination (DRA) is a useful method for the synthesis of amino derivatives from carbonyl compounds, amines, and H2. Precious-metal (Ru [130-132], Rh [133-137], Ir [138-142], Pd [143]) catalyzed reactions are well known to date. The first Fe-catalyzed DRA reaction was reported by Bhanage and coworkers in 2008 (Scheme 42) [144]. Although the reaction conditions are not mild (high temperature, moderate H2 pressure), the hydrogenation of imines and/or enam-ines, which are generated by reaction of organic carbonyl compounds with amines, produces various substituted aryl and/or alkyl amines. A dihydrogen or dihydride iron complex was proposed as a reactive intermediate within the catalytic cycle. 

The hydroaminations of electron-deficient alkenes with aniline or small primary alkylamines proceed at high conversions (85-95%, nnder mild conditions, 5 mol%, rt), giving exclnsively the anh-Markovnikov addition product. Secondary dialkyl or bnlky primary amines require longer reaction times. With amines containing P-hydrogens, no imine side-products were observed. 

The anionic rhodium complexes [(PR3)2Rh(NHPh)2] Li (see above) have been shown to catalyze (TON = 21) the condensation of aniline with styrene to give the expected amine and the corresponding imine (oxidative amination) (Eq. 4.37, TOP 0-07 h- ) [161]. 

Mechanishc studies indicated the possibihty of alkynylmercury chlorides as intermediates. They would react with amines to give 2-aminovinyhnercury chlorides which could be protonated to give enamines (or imines in the case of primary amines) (Scheme 4-13) [260]. 

Zincate reagents can add to imines with or without Lewis acid catalysis. Alkylimines require BF3 but imines of pyridine-2-carboxaldehyde react directly. If the imines are derived from chiral amines, diastereoselectivity is observed. Both a-phenylethyl amine and ethyl valinate have been tried. Higher enantioselectivity was observed with mixed magnesium reagents.175... 

The mercuration of ferrocenylimines with Hg(OAc)2 has been studied. - 6 Mercuration occurs selectively at the a-position relative to the imine group to afford compounds 86a-i (Scheme gy107,108 The regioselectivity of these reactions points to the directing role of the Lewis-basic imine functionality. Similar factors probably play a role in the formation of the ferrocenylketone and ferrocenylaldehyde derivatives 87a-f and 87g-j, respectively. These derivatives readily react with amines to afford the corresponding imines (Scheme 9). Presumably, the Lewis-acidic mercury center of the monomercurated ferrocenylketones and ferrocenylaldehydes activates the carbonyl functionality toward nucleophilic attack by the amine. 

Various chiral ligands with metal catalysts can be employed in the organosilane reduction of imines to amines. Many of these provide modest success. These include (oxazolino)diphenylphosphinoferrocene ligands with ruthenium,605 (—)-DIOP/Rh(I),606,607 3,3 -BINOL (l,l -bi-2-naphthol) and LiHMDS,608 and (S)-phenyl V-formylprolinamidc with trichlorosilane.609... 

The asymmetric hydrogenation of acyclic imines with the ansa-titanocene catalyst 102 gives the chiral amines in up to 92% ee.684,685 This same system applied to cyclic imines produces the chiral amines with >97% ee values.684,685 The mechanism of these reductions has been studied 686... 

Saaby S, Knudsen KR, Ladlow M, Ley SV (2005) The Use of a Continuous Flow-Reactor Employing a Mixed Flydrogen-Liquid Flow Stream for the Efficient Reduction of Imines to Amines. Chem Commun 23 2909-2911 Seebach D, Overhand M, Kilhnle FNM, Martinoni D, Oberer L, Hommel U, Widmer H (1996) Beta-Peptides Synthesis by Arndt-Eistert Homologation with Concomitant Peptide Coupling. Structure Determination by NMR and CD Spectroscopy and by X-ray Crystallography. Helical Secondary Structure of a Beta-Hexapeptide in Solution and its Stability Towards Pepsin. Helv Chim Acta 79 913-941... 

The TEAF system can be used to reduce ketones, certain alkenes and imines. With regard to the latter substrate, during our studies it was realized that 5 2 TEAF in some solvents was sufficiently acidic to protonate the imine (p K, ca. 6 in water). Iminium salts are much more reactive than imines due to inductive effects (cf. the Stacker reaction), and it was thus considered likely that an iminium salt was being reduced to an ammonium salt [54]. This explains why imines are not reduced in the IPA system which is neutral, and not acidic. When an iminium salt was pre-prepared by mixing equal amounts of an imine and acid, and used in the IPA system, the iminium was reduced, albeit with lower rate and moderate enantioselectivity. Quaternary iminium salts were also reduced to tertiary amines. Nevertheless, as other kinetic studies have indicated a pre-equilibrium with imine, it is possible that the proton formally sits on the catalyst and the iminium is formed during the catalytic cycle. It is, of course, possible that the mechanism of imine transfer hydrogenation is different to that of ketone reduction, and a metal-coordinated imine may be involved [55]. 

Hydrosilylation of imine compounds was also an efficient method to prepare amines. The hydrosilylation product TV-silylamines can readily be desilylated upon methanol or water treatment, yielding the corresponding amines. The amines can be converted to their corresponding amides by subsequent acyl anhydride treatment. The first attempt to hydrogenate prochiral imines with Rh(I) chiral phosphine catalysts was made by Kagan102 and others. These catalysts exhibited low catalytic activity, and only moderate ee was obtained. 

Mannich and related readions provide one of the most fundamental and useful methods for the synthesis of p-amino carbonyl compounds, which constitute various pharmaceuticals, natural products, and versatile synthetic intermediates.1271 Conventional protocols for three-component Mannich-type readions of aldehydes, amines, and ketones in organic solvents indude some severe side reactions and have some substrate limitations, espedally for enolizable aliphatic aldehydes. The dired synthesis of P-amino ketones from aldehydes, amines, and silyl enolates under mild conditions is desirable from a synthetic point of view. Our working hypothesis was that aldehydes could read with amines in a hydro-phobic reaction fidd created in water in the presence of a catalytic amount of a metal triflate and a surfactant to produce imines, which could then read with hydrophobic silyl enolates. 

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