Enamines stability

Possible role of thiamin diphosphate-dependent enzymes in enamine stabilization... 

Peptide synthesis. This 8-diketone reacts with an amino acid in the presence of methanolic potassium hydroxide to give the potassium salt of an azomethine, formulated as an enamine stabilized by hydrogen bonding. These derivatives can be... 

Imines and enamines, ° stabilized through hydrogen bonds, can also be effective prodrugs of primary amines (Figure 36.9). 

R, = CjHj, Rj, R3 = (0112)4] (45). Even the possibility of stabilization of the double bond by conjugation with an aromatic ring was not enough to overcome the steric repulsions. The enamine formed is probably an equilibrium product 46). 

Hydrolysis of an enamine yields a carbonyl compound and a secondary amine. Only a few rate constants are mentioned in the literature. The rate of hydrolysis of l-(jS-styryl)piperidine and l-(l-hexenyl)piperidine have been determined in 95% ethanol at 20°C 13). The values for the first-order rate constants are 4 x 10 sec and approximately 10 sec , respectively. Apart from steric effects the difference in rate may be interpreted in terms of resonance stabilization by the phenyl group on the vinyl amine structure, thus lowering the nucleophilic reactivity of the /3-carbon atom of that enamine. 

When trichloroacetic acid is used to protonate an enamine (17,17a), the salt has only limited stability. The trichloroacetate anion undergoes decarboxylation and the trichloromethyl anion which is generated adds to the iminium salt, giving an a-amino trichloromethyl derivative (8). 

The initial reaction between a ketene and an enamine is apparently a 1,2 cycloaddition to form an aminocyclobutanone adduct (58) (68-76a). This reaction probably occurs by way of an ionic zwitterion intermediate (75). The thermal stability of this adduct depends upon the nature of substituents Rj, R2, R3, and R. The enolic forms of 58 can exist only if Rj and/or R4 are hydrogens. If the enamine involved in the reaction is an aldehydic enamine with no 3 hydrogens and the ketene involved is di-substituted (i.e., R, R2, R3, and R4 are not hydrogens), then the cyclo-butanone adduct is thermally stable. For example, the reaction of dimethyl-ketene (61) with N,N-dimethylaminoisobutene (10) in isopropyl acetate... 

Enamines derived from 1-azabicycloalkanes, readily accessible by mercuric acetate oxidation of saturated bases (112), have been extensively studied recently (113-115). Since an immonium salt is formed during dehydrogenation, the composition of the liberated enamine mixture shows the relative stability of the various possible isomers. The study of infrared and NMR spectra has shown that the position of the enamine double bond is determined by factors similar to those determining the relative stability of simple olefins. 

The bulk of enamine studies since Stork s original publication have focused on establishing the breadth and limitations of individual substitution reactions and on extending the list of useful electrophiles. In addition, auxiliary studies have enriched our knowledge about the ambident nature of the vinyl nitrogen system, stereoelectronic factors governing its reactivity, its stability and spectroscopic properties. An increasing number of synthetic applications of these fundamental studies can be expected in future years. 

While the usual eonsequence of hydration of enamines is eleavage to a secondary amine and an aldehyde or ketone, numerous cases of stable carbinolamines are known (102), particularly in examples derived from cyclic enamines. The selective terminal hydration (505) of a cross-conjugated dienamine-vinylogous amide is an interesting example which gives an indication of the increased stabilization of the vinylogous amide as compared to simple enamines, which is also seen in the decreased nucleophilicity of the conjugated amino olefin-carbonyl system. 

Use of the imonium group for protection of enones was explored. Stability to peracids, lead tetraacetate, bromine, and acetic anhydride was claimed (727). The usual resistance of enamines (but not their salts) to additions of Grignard reagents was used for selective addition to a 3,17-diketosteroid by formation of the usual 3-monoenamine 728). 

Condensation of an aniline with a dione with loss of water provides enamine 16. Ketone protonation and cyclization forms 18 followed by loss of water provides quinoline 4. Some have suggested the formation of dication 19 as a requirement to cyclization. Cyclization of 19 to 20 and subsequent conversion to quinoline 4 requires loss of water and acid. Another rendering of the mechanism takes into account participation of an electron-donating group (EDG), which stabilizes intermediate 21. 

Likewise, amine functions on the azepine ring at an unsaturated carbon center behave as enamines and undergo hydrolysis under both acid and alkaline conditions to the benzazepinones.15,64 8084 However, hydrolysis of dimethyl l-acetyl-5-piperidino-l//-l-benz-azepine-3,4-dicarboxylate(18) yields not the benzazepinone but the tautomeric 5-hydroxy derivative 19.13 Presumably, the enol form is stabilized by intramolecular hydrogen bonding. 

Phenylsulphine prepared in situ from phenylmethanesulphinyl chloride and triethyl-amine reacted with 1 -morpholinocyclohexene to form the addition product 169 having the enamine structure218. A similar experiment with phenylsulphine and 2-pyrrolidinocyclo-hexene gave only 2-phenylmethanesulphinyl cyclohexanone 170. The latter is most probably formed by hydrolysis of the corresponding enamine sulphoxide upon isolation. The reaction of sulphines with enamines is apparently a stepwise process involving the transient formation of the dipolar intermediate 171 which is stabilized by proton transfer, giving the enamine sulphoxide. 

N-Acetylneuraminic acid aldolase (or sialic acid aldolase, NeuA EC 4.1.3.3) catalyzes the reversible addition of pyruvate (2) to N-acetyl-D-mannosamine (ManNAc (1)) in the degradation of the parent sialic acid (3) (Figure 10.4). The NeuA lyases found in both bacteria and animals are type I enzymes that form a Schiff base/enamine intermediate with pyruvate and promote a si-face attack to the aldehyde carbonyl group with formation of a (4S) configured stereocenter. The enzyme is commercially available and it has a broad pH optimum around 7.5 and useful stability in solution at ambient temperature [36]. 

The orbital phase theory was applied to the conformations of alkenes (a- and P-substituted enamines and vinyl ethers) [31] and alkynes [32], The conformational stabilities of acetylenic molecules are described here. 

A novel route to indoles and quinolines has been developed by sequential Wiltig and Heck reactions <96CC2253>. Thus, treatment of o-bromo- or iodo-lV-lrifluoroaceiylanilines (86) with a stabilized phosphorane affords the corresponding enamines 87 as a mixture of isomers. Cyclization to 88 is effected by heating with palladium acetate, tri phenyl phosphine, and bu.se. 

The preparation and investigation of the thietane oxide system (5a) is largely associated with stereochemical and conformational studies . The investigation of the thietane dioxides (5b) is substantially related to the chemistry of sulfenes , the [2 -I- 2] cycloaddition of which with enamines is probably the method of choice for the synthesis of 5b . The study of the thiete dioxide system (6) evolved, at least in part, from the recognition that the unstable thiete system 183 can be uniquely stabilized when the sulfur in the system is transformed into the corresponding sulfone , and that the thiete dioxide system is very useful in cycloadditions and thermolytic reactions. The main interest in the dithietane oxides and dioxides (7) appears to lie in the synthetic challenge associated with their preparation, as well as in their unique structural features and chemical behavior under thermolytic conditions . ... 

Scheme 2.23 provides some examples of conjugate addition reactions. Entry 1 illustrates the tendency for reaction to proceed through the more stable enolate. Entries 2 to 5 are typical examples of addition of doubly stabilized enolates to electrophilic alkenes. Entries 6 to 8 are cases of addition of nitroalkanes. Nitroalkanes are comparable in acidity to (i-ketocslcrs (see Table 1.1) and are often excellent nucleophiles for conjugate addition. Note that in Entry 8 fluoride ion is used as the base. Entry 9 is a case of adding a zinc enolate (Reformatsky reagent) to a nitroalkene. Entry 10 shows an enamine as the carbon nucleophile. All of these reactions were done under equilibrating conditions. 

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