Reaction with Secondary Amines Enamines

Secondary amines are compounds of the type R2NH. They add to aldehydes and ketones to form carbinolamines, but their carbinolamine intermediates can dehydrate to a stable product only in the direction that leads to a carbon-carbon double bond  

The mechanism of enamine formation in this example is shown in Mechanism 17.6. 

Write the structure of the carbinolamine intermediate and the enamine product formed in the reaction of each of the following  

Sample Solution (a) Nucleophilic addition of dimethylamine to the carbonyl group of propanal produces a carbinolamine  

Enamines are used as reagents in synthetic organic chemistry and are involved in certain biochemical transformations. 

The product of this dehydration is an alkenyl-substimted amine, or enamine. 

Mechanism 17.6 outlines the mechanism of the corresponding reaction of pyrrolidine and 2-methylpropanal. 

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Certain geminal difluoro groups arc easily aminolyzed yielding imines or enamines.3,20-24 An imine-enamine equilibrium is generally observed,13,25 - 28 which is dependent on the substrate and the amine used. Nevertheless, /i-imino carboxylic esters are predominantly obtained when a-hydrylperfluoro esters (e. g., 4) are reacted with primary amines, while reaction with secondary amines leads to the respective enamines.29,30... 

The effect of substituents on C(2) of vinyl bromide and on the amine of the palladium catalyst in the. S n reaction with secondary amines was examined. The catalyst formed from the reaction of Pd2(dba)3 with proazaphosphatrane (12) gave the best yields (>91%) of enamine.16 The. S n product formed with primary amines rearranged to give the imine as the product in yields of >86%. 

When the 3 -mesylate 141 was treated with secondary amines, enamines of type 142 were obtained, as anomeric mixtures. The authors theorise that a 2 -ketonucleoside is involved, formed by a hydride shift under metal-free conditions for a similar reaction starting from a D-/yxo-precursor see Vol. 28, p. 273. Hydrolysis of the a-anomer of 142 (-NR2 = morpholinyl) gave the a-2 -ketonucleoside 143, the structure of which was secured by crystallography of a derivative, and some earlier structural assignments were revised. ... 

II. Enamine formation reaction with secondary amines... 

The condensation of aldehydes or ketones with secondary amines leads to "encunines via N-hemiacetals and immonium hydroxides, when the water is removed. In these conjugated systems electron density and nudeophilicity are largely transferred from the nitrogen to the a-carbon atom, and thus enamines are useful electroneutral d -reagents (G.A. Cook, 1969 S.F. Dyke, 1973). A bulky heterocyclic substituent supports regio- and stereoselective reactions. 

Enamines are formed in the correspond mg reaction of secondary amines with aldehydes and ketones... 

The most versatile method for preparing enamines involves the condensation of aldehydes and ketones with secondary amines [Eq. (1)]. Mannich and Davidsen (/) discovered that the reaction of secondary amines with aldehydes in the presence of potassium carbonate and at temperatures near 0° gave enamines, while calcium oxide and elevated temperatures were required to cause a reaction between ketones and secondary amines, although usually in poor yield. The introduction by Herr and Heyl 2-4) of the removal of the water produced in the condensation by azeotropic distillation with benzene made possible the facile preparation of enamines from ketones and disubstituted aldehydes. 

Enamines in which the vinyl nitrogen system is in conjugation with another functional group can be obtained from reactions of secondary amines with /8-ketoaldehydes and -diketones or their monoenol ether or vinyl halide derivatives (41-46). 

The long known catalyses of some ketone condensation reactions by secondary amines, can be postulated to have their basis in the reactions of enamine intermediates with ketones. The unsuitability of methyl ketones for azeotropic enamine formation is based on this phenomenon. Recent studies in cyclization reactions have added further support to this concept (354). 

The most characteristic reaction of butadiene catalyzed by palladium catalysts is the dimerization with incorporation of various nucleophiles [Eq. (11)]. The main product of this telomerization reaction is the 8-substituted 1,6-octadiene, 17. Also, 3-substituted 1,7-octadiene, 18, is formed as a minor product. So far, the following nucleophiles are known to react with butadiene to form corresponding telomers water, carboxylic acids, primary and secondary alcohols, phenols, ammonia, primary and secondary amines, enamines, active methylene compounds activated by two electron-attracting groups, and nitroalkanes. Some of these nucleophiles are known to react oxidatively with simple olefins in the presence of Pd2+ salts. Carbon monoxide and hydrosilanes also take part in the telomerization. The telomerization reactions are surveyed based on the classification by the nucleophiles. 

Most of the work on the C-N bond-forming crosscoupling reactions has concentrated on the formation of aromatic C-N bonds. Recent studies show that the application of cross-coupling reactions to alkenyl halides or triflates furnished enamines (Scheme 19) (for palladium-catalyzed reaction, see 28,28a-28d, and for copper-catalyzed reaction, see 28e-28g). Brookhart et al. studied the palladium-catalyzed amination of 2-triflatotropone 109 for the synthesis of 2-anilinotropone 110.28 It was found that the reaction of 109 proceeded effectively in the presence of racemic BINAP and a base. As a simple method for the synthesis of enamines, the palladium-catalyzed reactions of alkenyl bromide 111 with secondary amine were achieved under similar conditions.2841 The water-sensitive enamine 112 was isolated as pure compound after dilution with hexane and filtration through Celite. The intramolecular cyclization of /3-lactam 113, having a vinyl bromide moiety, was investigated by Mori s... 

The reaction of thioaldehydes, generated from phosphonium ylides and sulphur with secondary amines such as dimethylamine, leads to thioamides. If the thioaldehydes possess a a-hydrogen atom enamines are produced (equation 103)326. 

In Section 7.7.2 we met enamines as products from addition-elimination reactions of secondary amines with aldehydes or ketones. Enamines are formed instead of imines because no protons are available on nitrogen for the final deprotonation step, and the nearest proton that can be lost from the iminium ion is that at the P-position. 

Stork Enamine Reaction Aldehydes and ketones react with secondary amines to form compounds called enamines. The general reaction for enamine formation can be written as... 

The course of the amination reaction is strongly dependent upon the nature of the amine used. With secondary amines, initial oxidation of the amine occurs to form an enamine attack of this intermediate at C-4 leads to a species such as 30 (Scheme 12), which ring-closes to form a pyrrole isomeric with that already described <2001TL5981>. 

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. 

Reaction of secondary amines with allenes to give enamines [170]. 

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