Aldehydes imine formation with primary

Imines are formed by condensation of aldehydes or ketones with primary amines, but they form with more difficulty than enamines.84,85 A special case of enamine preparation was described with 20-oxo-steroids.86 Treatment of these ketones with a primary amine gives a 20-ketimine, which is acetylated with acetic anhydride, with migration of the double bond and formation of 20-(A-acetylalkylamino)-J17(20)-pregnene (14) reduction of 14 with lithium aluminum hydride affords the enamine. 

Like acetal formation, the reaction of aldehydes and ketones with primary amines— compounds of the type RNH2 and ArNH2—is a two-stage process. Its first stage is nucleophilic addition of the amine to the carbonyl group to give a carbinolamine. The second stage is the dehydration of the carbinolamine to yield the isolated product of the reaction, an A-alkyl or A-aryl-substituted imine. 

Isomannide (80) was the core for a hexahydrofurofuran library." Primary amines were loaded onto solid-support by reductive amination and acylated with bromoacetic acid to give bromides 79 (Scheme 7.16). Alkylation of bromides 79 on solid-support with isomannide (80) gave the solid-supported alcohols 81. A Mitsunobu reaction with phthalimide (82) proceeded to furnish amines 83 in excellent yield and purity after removal of the protecting group." " Support-bound primary amines 83 were converted to secondary amines by stepwise imine formation with aldehydes 84 and reduction with sodium borohydride." The hindered secondary amines 85 were acylated with acid chlorides, sulfonyl chlorides, isocyanates, and isothiocyanates to yield 87 after cleavage from solid-support. 

Primary amines cannot be usefully prepared, by reductive alkylation, from lower members of the aliphatic aldehydes and ammonia owing to side-reactions (for instance, formaldehyde and ammonia give hexamethylenetetramine). For aldehydes with more than five carbon atoms, however, conversion to the corresponding amine gives 60% yieldsEven better yields are reported for aromatic aldehydes, presumably because of the greater ease of imine formation With an excess of aromatic aldehyde the reaction with ammonia invariably leads to formation of the secondary amine but with aliphatic compounds a mixture of primary and secondary amines is generally obtained. Alternatively, secondary amines can be prepared directly from primary amines (equation 35). 

The author envisioned that 1,3-diaminopropane would be an appropriate primary amine as it has an additional nucleophilic group that could sequentially form isoquinoline and pyrimidine rings (the reaction using 3-aminopropanol as the amine component 8 showed a promising result. However, the main product of this reaction was unstable and decomposed during purification). Thus, attempts to construct the pyrimido[2,l-a]isoquinoline framework was initiated with 2-ethynylbenzaldehyde la, paraformaldehyde 2, diisopropylamine 3a and 1,3-diaminopropane 8a (Table 1). Co-existence of two amines with two aldehydes in one-portion of the reaction would hamper the effective Mannich-type reaction of la, 2 and 3a and subsequent imine formation with 8a in the desired order. Therefore, the copper-catalyzed Mannich-type reaction of la, 2 (2 equiv) and 3a (2... 

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. 

Mechanism of imine formation by reaction of an aldehyde or ketone with a primary amine. 

Reaction of an aldehyde or ketone with a secondary amine, R2NH, rather than a primary amine yields an enamine. The process is identical to imine formation up to the iminium ion stage, but at this point there is no proton on nitrogen that can be lost to form a neutral imine product. Instead, a proton is lost from the neighboring carbon (the a carbon), yielding an enamine (Figure 19.10). 

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. 

Aldehydes and ketones can react with primary and secondary amines to form Schiff bases, a dehydration reaction yielding an imine (Reaction 45). However, Schiff base formation is a relatively labile, reversible interaction that is readily cleaved in aqueous solution by hydrolysis. The formation of Schiff bases is enhanced at alkaline pH values, but they are still not stable enough to use for crosslinking applications unless they are reduced by reductive amination (see below). 

Because of their significant electrophilic character, aldehydes are often unstable and will react with nucleophiles. For example, a common reaction of aldehydes is the formation of a hemiaminal with amines. If the amine is a primary amine, the hemiaminal can dehydrate to form an imine as shown in Figure 21. The reaction of aldehydes with primary and secondary amines is a well-studied reaction pathway because it is a common reaction pathway of reducing sugars and amino acids, and this reaction pathway is known as the Maillard reaction (40). In the case of amino acids and sugars, this reaction leads to discoloration, or browning. This reaction will be discussed in greater detail in the Amines-Maillard Reaction section. 

The key to the success of the aza-enolates is that the imine is first formed from the aldehyde with the primary amine, a relatively weak base, and under these conditions imine formation is faster than self-condensation. Only after the imine is formed is LDA added when self-condensation cannot occur simply because no aldehyde is left. 

A. 15.1.2.2 Imines and Enamines. Primary amines react with aldehydes and ketones to form the corresponding A-alkyl- or A-aryl-substituted imines (R— CO—R + R"—NH2 R—C=(NR")—R + H2O). Imine formation is a... 

Mechanism of imine formation by reaction of a ketone or aldehyde with a primary amine. The key step is nucleophilic addition to yield a carbinolamine intermediate, which then loses water to give the imine. 

The reaction of a primary amine with a ketone to form an imine is generally quite straightforward, with the techniques typically used for water removal in the formation of enamines (see Section 4.1.2.1) also applicable here. As with the formation of enamines from aldehydes, preparation of the corresponding aldehyde imines can be difficult, especially with relatively unhindered aldehydes where formation of the double amine addition product can occur. However, these aminals often undergo loss of one amine unit thermally (typically during distillation) to generate the imine (Scheme 16). ... 

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