Enamine preparation

The stereochemical assignment is based on the comparison of the product with the pure cis and trans isomers (128 and 129) of the enamine prepared by the base-catalyzed elimination of the mesitoate esters of the d/-erythro-2-(4-morpholino)-l,2-diphenylethanol (130) and the <7/-threo-2-(4-morpho-lino)-l,2-diphenylethanol (131). 

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-... 

Enamines prepared from the more basic amines are alkylated more easily and in higher yield, but yields are also affected by the ease of formation of an exocyclic double bond in the transition state (32). Thus the enamines derived... 

The enamine prepared from acetone and dimethylamine is shown here in its lowest-energy form. 

Problem 23.19 What products would result after hydrolysis from reaction of the enamine prepared from cydopentanone and pyrrolidine with the following a./3-unsatiualed acceptors (a) CH2=CHC02Et (b) H2C = CHCHO (c) CH3CH=CHCOCH3... 

The imines are prepared by 16-12. The enamine salt method has also been used to give good yields of mono a alkylation of a,P-unsaturated ketones. Enamines prepared from aldehydes and butylisobutylamine can be alkylated by simple primary alkyl halides in good yields. N-alkylation in this case is presumably prevented by steric hindrance. 

Enamines and Formamidines. Enamines, prepared from methylpyridines, methyl-pyridazines, methylpyrimidines or methyltriazine, and A, A -dimethylformamide dimethylacetal or ferf-butoxybis(dimethylamino)methane, react with 2-phenyl-5(4//)-oxazolone 146 to afford the unsaturated 5(477)-oxazolones 199 and 201 that are intermediates in the synthesis of fused pyridones 200 and pyridotriazi-nones 202, respectively (Scheme 7.61). ... 

Chiral enamines prepared from /f-oxo esters and the tcrt-butyl ester of (.V)-valine are lithiated by LDA (—78 °C, toluene or THF, 1 h)18 19. Both enantiomers of the alkylation product are obtained with a high degree of diastercoselectivity starting from one auxiliary when the reaction is performed under the addition of different ligands (see Table 6). Addition of one equivalent of hexamethylphosphoric triamide (1IMPA) causes coordination of the lithium atom and alkylation from the top side18. 

Early investigations have demonstrated that aldehydes and ketones can be enantioselectiveiy a-alkyl-ated via Michael reactions of the corresponding enamines, prepared from proline-derived secondary amines.149-156 However, optical purities of the products were generally low and never exceeded 59% ee.iS1 This kind of asymmetric a-alkylation could later be improved, allowing for example the preparation of compound (141) with high ee (Scheme 51).156-160... 

Condensation of aldehydes and ketones with secondary amines in the presence of dehydrating agents (often potassium carbonate69-71) represents a general method of enamine preparation. By this procedure ketones afford the enamines directly, whereas aldehydes are converted in the first step into diamino derivatives which decompose on distillation to give the enamine and a molecule of the secondary amine. In the case of ketones and disubstituted acetaldehydes, the water formed by the reaction can be removed by azeotropic distillation with benzene, toluene, or xylene.27,31,72-75 In the case of derivatives of aromatic aldehydes, the formation of intermediary carbinolamines 76 is sometimes observed. 

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. 

Alkylation of enamines prepared from aldehydes was studied by Elkik,210 Opitz and Mildenberg,211 and Williamson 212 and alkylation of enamines prepared from ketones by Stork et al.75 These investigators demonstrated that the ease of alkylation depends on the basicity of the enamine in question. Enamines prepared from the more basic pyrrolidine are alkylated more readily than those obtained from morpholine. Better yields of the enamines (44) from pyrrolidine are obtained, in contrast to the preparations (45) from piperidine (which are bases about as strong as pyrrolidine) this may result from the stabilizing influence of the exocyclic double bond in the polarized form of the pyrrolidine derivative. 

The enamines prepared from acetaldehyde or monosubstituted acetaldehydes undergo self-condensation in the reaction mixture very readily so that alkylation is practically impossible. Enamines prepared from disubstituted aldehydes are exclusively iV-alkylated on treatment with aliphatic alkyl halides,218 whereas allyl halides cause... 

Enamines obtained from a,/3-unsaturated carbonyl compounds are usually alkylated at C(2)220,221 (Scheme 7). Analogous enamines prepared from A 4-3-oxosteroids, however, afford only quaternary ammonium salts.201... 

Sometimes acid anhydrides may be used as acylating reagents. The mixed anhydride of formic and acetic acid reacts with the enamines prepared from cyclohexanone to give 50% of hydroxymethylene-cyclohexanone.212 An intramolecular acylation with an ester (70) has also been reported.249... 

Treatment of 1-morpholino-l-cyclohexene with ketene gives l-morpholino-2-acetyl-l-cyclohexene251 as the main product, whereas enamines prepared from aliphatic aldehydes yield cyclo-butanones.252,253 Ketene may be generated directly in the reaction medium from acid chlorides and triethylamine. 

Stork has used the addition of a,/ -unsaturated aldehydes, ketones, esters, and nitriles to enamines prepared from ketones and pyrrolidine, piperidine, or morpholine for the synthesis of a-substituted carbonyl compounds264 266 (Scheme 9). 

Oxygen may be added by means of peracids to the double bond of enamines prepared from 20-oxosteroids. The 17,20-epoxides obtained may be readily hydrolyzed to 17a-hydroxy-20-oxosteroids.88 Schiff bases afford oxaziranes on treatment with peracids.285 By means... 

Enamines are very reactive compounds, easily accessible and of great importance in organic chemistry. The regiochemistry and stereochemistry of enamine preparation and the reactivity of the produced enamines depends strongly on structure, stereochemistry and electronic considerations which are of particular importance. Consequently, it is sometimes found that the product distribution in an enamine reaction depends not only on the relative stability of various enamine isomers but also on their relative reactivity. 

The general procedures for the preparation of enamines, such as condensation of an open-chain aldehyde with a secondary amine in the presence of potassium carbonate or azeotropic removal of water from a solution of a ketone and secondary amine in benzene (frequently in the presence of an acid catalyst), fail to incorporate the desirable feature of stereospecificity. The spectra of a series of enamines prepared from both aldehydes and ketones indicated that the Zs-isomer predominated, but not to the total exclusion of the Z-isomer. 

Enamines prepared from / -diketones and ethyl acetoacetate8 also lose a radical by allylic cleavage. When R = CH3 or OCH3 (Scheme 5), 9, 10 and 11 lose preferentially CH3 or OCH3 radicals9, respectively. 

Asymmetric alkylation of a-alkyl-P-keto esters. The sense of asymmetric alkylation of the chiral enamines prepared from (S)-valine /-butyl ester with a-alkyl-P-keto esters is markedly controlled by the solvent. Thus alkylation of the anion 1, prepared with LDA in toluene, with CH,I in the presence of HMPT (1 equiv.) results in (R)-2 in 99% ee, whereas alkylation in THF (2 equiv.) results in (S)-2 in 92% ee. The effect of HMPT is general for a variety of electrophiles depending on the electrophile, dioxolane... 

Enamines are readily available ketone derivatives." Exposure of these compounds to certain transition metal salts has been shown to produce a-oxygenated imines which are rapidly hydrolyzed to their ketone counterparts. Thus, for example, morpholino enamines, prepared in situ, are a-acetoxylated on treatment with thallium triacetate. The process is thought to involve either direct nucleophilic extraction of an acetate unit or the intermediacy of an organothallium species which subsequendy undergoes anchimerically assisted intramolecular acetoxy migration to generate the a-acetoxyimine (Scheme IS). 

Tho i njugate addition of a carbon oucJeophJle to an oji -unsaturated acceptor is known as the Michael reaction. The best Michael reactions take place between unusually acidic donors (3-kclo estcrit or /3-diketones) and unhindered M -unaaturated acceptors. Enamines, prepared by reaction of a ketone with a disuh tituted amine, are also good Michael donors. 

The intermediate in this reaction could be either the prostereogenic enolate or the chiral enamine formed in situ. In an attempt to distinguish between these pathways, the chiral enamine prepared from methyl (S)-prolinate was allowed to react with methyl A-phenylseleno-(S)-prolinate. The isolated 2-phenyl-2-phenylselenopropanal had the same enantiomeric excess as that obtained in the direct a-selenenylation of racemic 2-phenylpropanal. This result clearly indicates that the intermediacy of the chiral enamine cannot be excluded7. 

Ethoxycarbonylamino)cyclohcxanoncs were obtained in low yield by hydrolysis of the aziridines formed by the addition of ethoxycarbonyl nitrene, generated in situ from 4-nitro-phenylsulfonyl carbamates, to enamines prepared from substituted cyclohexanones61,62. By the same method, optically active 2-(ethoxycarbonylamino)cyclohexanone 3 was prepared in low yield from the enamine 1 derived from an optically active 2-substituted pyrrolidine63. 

Problem 23.19. What products would result alter hydrolysis from reaction of the enamine prepared... 

The stereoselective allylation of aldehydes was reported to proceed with allyltrifluorosilanes in the presence of (S)-proline. The reaction involves pentacoordinate silicate intermediates. Optical yields up to 30% are achieved in the copper-catalyzed ally lie ace-toxylation of cyclohexene with (S)-proline as a chiral ligand. The intramolecular asymmetric palladium-catalyzed allylation of aldehydes, including allylating functionality in the molecules, via chiral enamines prepared from (5)-proline esters has been reported (eq 15). The most promising result was reached with the (S)-proline allyl ester derivative (36). Upon treatment with Tetrakis(triphenylphosphine)palladium(0) and PPh3 in THF, the chiral enamine (36) undergoes an intramolecular allylation to afford an a-allyl hemiacetal (37). After an oxidation step the optically active lactones (38) with up to 84% ee were isolated in high chemical yields. The same authors have also reported sucessful palladium-catalyzed asymmetric allylations of chiral allylic (S)-proline ester enamines" and amides with enantiomeric excesses up to 100%. 

Ketones and secondary amines furnish enamines in the presence of TiCl4 [580,581]. The preparation of a functionalized enamine shown in Eq. (251), in which the acetal moiety is retained in the product, illustrates the applicability of this reaction [582]. Enamines prepared by this method are summarized in Table 24. Application to an intramolecular reaction is also found in Table 24. If formation of the enamine is thermodynamically preferred to formation of the isomeric imine, the former becomes the product even in the reaction of a ketone, a primary amine, and TiCl4, as shown in Eq. (252) [583], in which the resulting enamine was, after acetylation, isolated as the enamide. 

The enamine prepared fi m acetone and dimethylamine is shown below in its low energy form. 

Problem 23.17 What products would result (after h.vdrolyais) from reaction of the enamine prepared from cyclopentanonc and pyrrolidine with the followinij aj3-unsaturated acceptors (a) Ethyl propenoate (b) Propenal (acrolein)... 

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