Aldehyde condensation enamines

The addition of phenylisocyanate to aldehyde-derived enamines resulted in the formation of aminobutyrolactams (438,439). As aminal derivatives these produets can be hydrolyzed to the linear aldehyde amides and thus furnish a route to derivatives of the synthetically valuable malonaldehyde-acid system. With this class of reactions, a second acylation on nitrogen becomes possible and the six-membered cyclization products have been reported (440). Closely related to the reactions of enamines with isocyanates is the condensation of cyclohexanone with urea in base (441). 

This topological rule readily explained the reaction product 211 (>90% stereoselectivity) of open-chain nitroolefins 209 with open-chain enamines 210. Seebach and Golinski have further pointed out that several condensation reactions can also be rationalized by using this approach (a) cyclopropane formation from olefin and carbene, (b) Wittig reaction with aldehydes yielding cis olefins, (c) trans-dialkyl oxirane from alkylidene triphenylarsane and aldehydes, (d) ketenes and cyclopentadiene 2+2-addition, le) (E)-silyl-nitronate and aldehydes, (f) syn and anti-Li and B-enolates of ketones, esters, amides and aldehydes, (g) Z-allylboranes and aldehydes, (h) E-alkyl-borane or E-allylchromium derivatives and aldehydes, (i) enamine from cyclohexanone and cinnamic aldehyde, (j) E-enamines and E-nitroolefins and finally, (k) enamines from cycloalkanones and styryl sulfone. 

The asymmetric a-chlorination of aldehydes has also be achieved using SOMO catalysis (Scheme 13.21) [49]. In these reactions, saturated aldehydes condensed with MacMillan s imidazolidinone organocatalyst to form enamines. The oxidant combination of Cu(TFA)2 and Na2S20g oxidized the enamine to the radical cation (inset in Scheme 13.21), the reactive intermediate in this transformation containing... 

With bulky secondary amines, for example, morpholine, diisopropylamine, and er -butylamine, the reaction may stop at the stage of the corresponding aldehydes or enamines [28]. It seems that the condensation of an intermediarily formed aldehyde with the amine is the slowest step of the whole reaction sequence. Branched aldehydes react slower than linear aldehydes. 

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. 

Mills and Smith (504) were the first, in 1922, to develop a systematic study of the reactivity of methyl groups fixed on nitrogen-containing heterocycles. While in alkylpyridines the 2- (or 6) and 4-positions are activated, only the 2-position in thiazole corresponds to an enhanced reactivity of the methyl groups in condensation with aldehydes 4- and 5-methylthiazoles bear inert methyl groups. Quatemization of the thiazole nitrogen enhances still further the reactivity of the methyl in the 2-position (cf. Chapter IX), but it does not increase the reactivity of a methyl group in the 4-position (504). The authors invoke the possibility for 2- (and 6) methylpyridine and 2-methylthiazole to pass, to some extent, into the reactive enamine form (245), while 4-methylthiazole could adopt such a structure only with the participation of an unusual formula such as 247 (Scheme 112). 

Enamines from the Condensation of Aldehydes and Ketones with Secondary Amines. ... 

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. 

The next seven references are cited not because of the experimental procedures described but because they indicate diversification in the types of enamines prepared and studied. Both Paquette (25) and Kasper 26) have condensed 2,5-methylene-l,2,5,6-tetrahydrobenzaldehyde (5-nor-bornene-2-carboxyaldehyde) (2) with several cyclic and open-chain aliphatic secondary amines. Kasper studied the ratio of endo to exo aldehyde formed upon hydrolysis of these enamines and the dihydro enamines. Paquette investigated the addition of sulfene to the enamines. -Fluoro-... 

The secondary amines used in the preparation of enamines have been primarily simple dialkylamines or cyclic amines of five- or higher-membered rings. Azetidine (4) yields a stable enamine with cyclopentanone (28). No simple enamines formed by condensation of ethylenimine (5) or a substituted ethylenimine with an aldehyde or ketone have been reported. 

A by-product of the reaction between an enamine, elemental sulfur, and carbon disulfide is an a-dithiopyrone. This by-product is the result of the condensation of two enamine molecules with one carbon disulfide molecule. In the case of aldehydic enamines, the reaction probably proceeds through... 

Thus the reactions of cyclic or acyclic enamines with acrylic esters or acrylonitrile can be directed to the exclusive formation of monoalkylated ketones (3,294-301). The corresponding enolate anion alkylations lead preferentially to di- or higher-alkylation products. However, by proper choice of reaction conditions, enamines can also be used for the preferential formation of higher alkylation products, if these are desired. Such reactions are valuable in the a substitution of aldehydes, which undergo self-condensation in base-catalyzed reactions (117,118). Monoalkylation products are favored in nonhydroxylic solvents such as benzene or dioxane, whereas dialkylation products can be obtained in hydroxylic solvents such as methanol. The difference in products can be ascribed to the differing fates of an initially formed zwitterionic intermediate. Collapse to a cyclobutane takes place in a nonprotonic solvent, whereas protonation on the newly introduced substitutent and deprotonation of the imonium salt, in alcohol, leads to a new enamine available for further substitution. 

Similarly, methyl vinyl ketone has been added to enamines derived from aldehydes (3,321,324-327) and ketones (3,328), providing a useful extension of the Robinson annelation reaetion. Condensations of enamines with other a, 3-unsaturated ketones can give a variety of diketones (329). 

ENAMINES IN ORGANIC SYNTHESIS C. Condensations with Aldehydes and Ketones... 

The reactions of enamines with aldehydes (329,350) are noteworthy in that they provide a route to the monobenzylidene derivatives of five- to seven-membered eyclic ketones as well as a method for the formation of other a, 9-unsaturated carbonyl compounds, in fair to good yields. The condensation of benzaldehyde with enamines is also involved in the formation of 3,5-dibenzylpyridine from piperidine and benzaldehyde (191-193). 

The condensation of a vinylogous formamide with an enamine has been applied to an aza azulene synthesis (351). The point of attachment of the aldehyde to the enamine in condensations with indolenin derived poly-enamines was found to favor the second double bond (352,353). 

The condensation of sulfonyl chlorides with enamines (452,453) derived from aldehydes and ketones has led to four-membered-ring sulfones, presumably through such intermediates (454-464). Open sulfonation products have also been obtained, particularly from ketone-derived enamines and from a-disubstituted sulfonyl chlorides. 

The Combes reaction is a sequence of the following reactions (a) condensation of an arylamine 1 with a 1,3-diketone, keto-aldehyde or dialdehyde 2 providing enamine 3, and (b) cyclodehydration to provide quinoline 4. 

We have previously discussed that keto-aldehydes react with anilines first at the aldehyde carbon to form the aldimine. Subsequent condensation with another aniline formed a bis-imine or enamino-imine. The aniline of the ketimine normally cyclizes on the aldimine (24 —> 26). Conversely, cyclization of the aldimine could be forced with minimal aniline migration to the ketimine using PPA (30 —> 31). The use of unsymmetrical ketones has not been thoroughly explored a few examples are cited below. One-pot enamine formation and cyclization occurred when aniline 48 was reacted with dione 49 in the presence of catalytic p-TsOH and heat. Imine formation occurred at the less-hindered ketone, and cyclization with attack on the reactive carbonyl was preferred. ... 

Villsmeier reaction on the dimethylacetal of methoxyacetaldehyde (141) with phosgene and dimethyIformamide affords the acrolein derivative, 142. Condensation of this with guanidine gives the pyrimidine, 143. (The enamine can be viewed as a latent aldehyde-the dimethylamino group is probably lost in the course of an addition elimination reaction with one of the guanidine groups.) This pyrimidine serves as starting material for sulfameter (111). ... 

Azines have been prepared by initial condensation of diethoxyphosphinyIhydrazine anions with aldehydes or ketones (Scheme 9). Phosphoryl azides undergo 1,3-dipolar cycloaddition to 2-tetralone enamines to give triazolines, possibly en route to amidines. A full paper on the addition of diethyl dibromophosphoramidate to alkenes(leading to the synthesis of 2-bromoalkylamines) has appeared. ... 

MgS04, the tetracycles 2-648 were obtained with excellent diastereoselectivity in reasonable yield. The reaction presumably starts with a condensation of the aldehydes 2-645 with the benzyl-protected amine moiety of 2-644 to give an iminium ion which can subsequently cyclize to afford the spirocyclic intermediates 2-646. A [3,3] sigmatropic Cope rearrangement then forms the nine-membered cyclic enamines 2-647 which, after protonation, act as the starting point for another indole iminium cyclization to provide the tetracycles 2-648 via 2-647. 

Carbonyl alkylation and condensation reactions are always of great value in synthesis, and the formation of o-ANIS ALDEHYDE via 4,4-dimethyl-2-oxazoline, 2,2-DIMETHYL-3-PHENYLPROPION-ALDEHYDE via alkylation of the magnesio-enamine salt and threo-4-HYDROXY-3-PHENYL-2-HEPTANONE via a directed aldol... 

Secondary and tertiary amines can be obtained if the hydroformylation of olefins is conducted in the presence of primary and secondary amines under elevated hydrogen partial pressures. Here the rhodium catalyst is involved in both steps, the hydroformylation of an olefin as well as the hydrogenation of the imine or enamine resulting from a condensation of the oxo-aldehyde with the amine (Scheme 14). This combination of hydroformylation and reductive amination is also known as hydroaminomethylation and has been applied to the synthesis of various substrates of pharmaceutical interest [55-57] as well as to the synthesis of macrocycles [60-63] and dendrimers [64,65]. 

The condensation of aldehydes and ketones with aminoacetonitriles, although it requires more vigorous soliddiquid catalytic conditions to produce the cyano-enamines, is preferable in many respects to the traditional Wittig-Horner or Peterson procedures [45]. Hydroxyalkylphosphonates are obtained from the catalysed aldol condensation of nitromethane with acylphosphonates [46]. 

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