Enamines with carbonyls

R,2S)-Ephedrine has found most application, e.g., as a catalyst in photochemical proton transfer reactions (Section D.2.1.). and as its lithium salt in enantioselective deprotonations (Section D.2.1.). The amino function readily forms chiral amides with carboxylic acids and enamines with carbonyl compounds these reagents perform stereoselective carbanionic reactions, such as Michael additions (Sections D.1.5.2.1. and D. 1.5.2.4.), and alkylations (Section D.1.1.1.3.1.). They have also been used to obtain chiral alkenes for [1 +2] cycloadditions (Section D. 1.6.1.5.). 

Since the first seminal reports by Stork on the use of secondaiy amines for the generation of enamines with carbonyl compounds, it was soon recognised that enamines derived from pyrrolidine were among the most reactive ones... 

The unique nucleophilic reactivity of pyrrohdines, which form iminium compounds and enamines with carbonyl compounds more readily than other secondary or primary amines, had been recognized in the seminal studies of Stork and Brown (a) G. Stork, R. Terrell, J. Szmuskovicz, J. Am. Chem. Soc. 1954, 76,2029 (b) G. Stork, H. K. Landerman, J. Am. Chem. Soc. 1956, 78, 5128 (c) H. C. Brown, J. Chem. Soc. 1956, 1248. 

Primary and secondary amines also react with epoxides (or in situ produced episulfides )r aziridines)to /J-hydroxyamines (or /J-mercaptoamines or 1,2-diamines). The Michael type iddition of amines to activated C—C double bonds is also a useful synthetic reaction. Rnally unines react readily with. carbonyl compounds to form imines and enamines and with carbo-tylic acid chlorides or esters to give amides which can be reduced to amines with LiAlH (p. Ilf.). All these reactions are often applied in synthesis to produce polycyclic alkaloids with itrogen bridgeheads (J.W. Huffman, 1967) G. Stork, 1963 S.S. Klioze, 1975). 

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). 

An a-oximino enamine was formed by the reaction of nitrosyl chloride and triethylamine with morpholinocyclohexene 494). Oxime functions have also been introduced into carbonyl conjugated enamines with isoamyl nitrite or NjOj 495). 

In the reduction of imines and enamines with hydrogen telluride and sodium hydrogen telluride, hydrolysis leading to primary amines and carbonyl compounds is frequently competitive with the reduction. This undesired side reaction is minimized by the addition of triethylamine, in the case of hydrogen telluride. ... 

Resin-bound amines can be converted into imines [710,711] or enamines by reaction with carbonyl compounds (Entries 6 and 7, Table 3.39). Resin-bound enamines have also been prepared by Michael addition of resin-bound secondary amines to acceptor-substituted alkynes [712], by Hg(II)-catalyzed addition of resin-bound secondary amines to unactivated alkynes [713], by addition of C-nucleophiles to resin-bound imino ethers [714], and by chemical modification of other resin-bound enamines [712,713,715], Acceptor-substituted enamines ( push-pull alkenes) are not always susceptible to hydrolytic cleavage by TFA alone and might require aqueous acids to undergo hydrolysis [716]. 

With regard to the mechanism of this new type of reaction, the Jorgensen group postulated enamine formation, by addition of the catalyst to the nitrone, followed by hydroxylamine elimination [132], Subsequent aldol-type reaction of this enamine with the carbonyl component and release of the proline catalyst by exchange... 

The formation of alkenes can happen when a BSMA derivative is partially desilylated in the presence of a carbonyl compound, finally giving the corresponding enamine. Many examples have been given of this useful and easily applicable technique. Starting from benzotriazole derivatives, the corresponding enamines are obtained after reaction with carbonyl compounds in the catalytic presence of fluoride anion.156... 

L-Proline is perhaps the most well-known organocatalyst. Although the natural L-form is normally used, proline is available in both enantiomeric forms [57], this being somewhat of an asset when compared to enzymatic catalysis [58], Proline is the only natural amino acid to exhibit genuine secondary amine functionality thus, the nitrogen atom has a higher p Ka than other amino acids and so features an enhanced nucleophilicity compared to the other amino acids. Hence, proline is able to act as a nucleophile, in particular with carbonyl compounds or Michael acceptors, to form either an iminium ion or enamine. In these reactions, the carboxylic function of the amino acid acts as a Bronsted acid, rendering the proline a bifunctional catalyst. 

The survey in Figure 9.23 shows that N nucleophiles can react with carbonyl compounds in the following ways (1) An addition to the C=0 double bond followed by an SN1 reaction leads to the formation of AW-acetals (details Section 9.2.4). (2) An addition to the C=0 double bond is followed by an El reaction by which, amongst others, enamines are formed (details Section 9.3). (3) Imines are produced. We still need to discuss whether the reaction of O nucleophiles with carbonyl compounds also gives us two options—parallel to the two possibilities (1) and (2) mentioned above. According to Figure 9.12 alcohols and carbonyl compounds always afford 0,0-acetals—through an addition and an SN1 reaction (details Section 9.2.2). 

Diphenylcyclopropenone is the first stable molecule prepared which has a carbonyl group in a three-membered ring. In a very real sense the compound has aromatic character and is fairly stable.4 An interesting cycloaddition reaction of enamines with diphenylcyclopropenone has been reported.7... 

Secondary amines react with carbonyl compounds to form enamines ... 

Stable primary enamines have been observed in the case of a- or / -substitution of enamines by carbonyl or ester groups. The reduction of ethyl 3-methyl-2-nitro-2-butenoate (24) with aluminium amalgam57 afforded ethyl 2-amino-3-methyl-2-butenoate (25), the enamine form, whereas the treatment of ethyl 3-methyl-2-oxobutanoate (26) with triphenylphosphinimine yielded ethyl 2-imino-3-methylbutanoate (27), the imino form, both of which were characterized by their IR and 1H NMR spectra. These two isomers,... 

The 13C-, 15N- and -NMR spectral data for a series of simple l-amino-2-nitroalkenes are collected in Table 30. The greater electron-withdrawing character of the nitro group as compared with carbonyl results in downfield shifts of the resonances of C(2) ( + 10 to +14 ppm), the enaminic nitrogen ( + 23.2 to + 27.4 ppm) and the olefinic protons [ + 0.8 to +1.0 ppm for H(l) +1.5 to = 1.8 ppm for H(2)] of 2-nitroenamines with respect to enaminones. This deshielding does not affect C(l), which has in fact a lower chemical shift ( — 5.5 to — 10.2 ppm) in 2-nitroenamines. The NMR spectra show that 2-nitroenamines with a primary or a secondary amino groups exist in solution as solvent-dependent equilibrium mixtures of E- and Z-isomers. The... 

The first reported experiments concerned the protonadon of enamines with (2) ,3) )-DPTA leading, after hydrolysis of the iminium salts formed in situ, to opdcally acdve carbonyl compounds. Starting from the (Z)- and ( )-morpholino enamines of 2-phenylpropanal, it was possible to establish, in spite of... 

The mechanisms illustrate why the reaction of 1° amines with carbonyl compounds forms imines, but the reaction with 2° amines forms enamines. In Figure 21.10, the last step of both mechanisms is compared using cyclohexanone as starting material. The position of the double bond depends on which proton is removed in the last step. Removal of an N—H proton forms a C=N, whereas removal of a C-H proton forms a C=C. 

Because imines and enamines are formed by a set of reversible reactions, both can be converted back to carbonyl compounds by hydrolysis with mild acid. The mechanism of these reactions is exactly the reverse of the mechanism written for the formation of imines and enamines. In the hydrolysis of enamines, the carbonyl carbon in the product comes from the hybridized carbon bonded to the N atom in the starting material. 

Preparation of imines and enamines from carbonyl compounds and amines can be achieved with a dehydrating agent under acid/base catalysis [563]. Basically, primary amines afford imines unless isomerization to an enamine is favored as a result of conjugation, etc (see Eq. 252), and secondary amines afford iminium salts or enamines. These transformations can be conducted efficiently with a catalytic or stoichiometric amount of a titanium salt such as TiCU or Ti(0-/-Pr)4. Equation (247) illustrates an advantageous feature of this method in the imination of a hindered ketone. f-Butyl propyl ketone resisted the formation of the imine even by some methods reported useful for sterically hindered ketones [564,565]. The TiCU-based method works well, however, for this compound, giving the desired imine in high yield within a relatively short reaction period [566]. Imine derivatives such as iV-sulfonylimines could be... 

Nitrogen has an unshared electron pair so an enamine could function as an enolate ion. Many people had had this idea before, but nobody had done anything synthetically useful with it. We were extremely lucky because the kind of reaction we tried, the monoalkylation of a ketone enamine with an alkyl halide, is actually poor with enamines with one exception, and, by chance, it was that exception that we tried first and it worked very well. The particular molecule was a so-called -tetralon. These ketones give 90% yield by the enamine alkylation process. This was in the mid-1950s and we published a general review in 1963 [Stork, G. Brizzolara, A. H. Landesman, H. K. Szmuszkovicz, J. Terrell, R. The enamine alkylation and acylation of carbonyl compounds. /. Am. Chem. Soc. 1963,... 

The condensation of N-alkylated silylmethylamines with carbonyl compounds would form N-silylmethyliminium hydroxide intermediates 46, whose desilylation leading to azomethine ylides 30 is expected to occur spontaneously. This process [Eq. (6)] is closely related to the above enamine process and looks promising. However, no such reaction has yet been reported. 

Computational studies suggest that the mechanism of the proline catalyzed aldol cyclization is best described by the nucleophilic addition of the neutral enamine to the carbonyl group together with hydrogen transfer from the proline carboxylic acid moiety to the developing alkoxide. A metal-free partial Zimmerman-Traxler-type transition state involving a chair-like arrangement of enamine and carbonyl atoms and the participation of only one proline molecule has been established [118,119]. On the basis of density functional theory (DFT) calculations Cordova and co-workers [120,121] have studied the primary amino acid intermolecular aldol reaction mechanism. They demonstrated that only one amino acid molecule is involved in the... 

Stork enamine reaction The reaction of an enamine with an alkyl halide that results in the alkylation of the (P-carbon. Usually followed by hydrolysis of the resultant imine salt to give a carbonyl functionality at the a-carbon. 

A further example of the reactivity of (1) with carbonyl-activated methylene compounds is the reaction of (1) with cycloallcanones.4 Thus (1) reacts with cycloalkanones (9) in refluxing chloroform to give immonium chlorides (10), which on hydrolysis give amides (11) in overall yields of about 70-85%. The reagent (1) reacts with enamines... 

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