Enamines as nucleophiles

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. 

There is a distinct relationship between keto-enol tautomerism and the iminium-enamine interconversion it can be seen from the above scheme that enamines are actually nitrogen analogues of enols. Their chemical properties reflect this relationship. It also leads us to another reason why enamine formation is a property of secondary amines, whereas primary amines give imines with aldehydes and ketones (see Section 7.7.1). Enamines from primary amines would undergo rapid conversion into the more stable imine tautomers (compare enol and keto tautomers) this isomerization cannot occur with enamines from secondary amines, and such enamines are, therefore, stable. 

The most prominent property of enamines is that the ( -carbon can behave as a carbon nucleophile. 

This is a consequence of resonance overlap of lone pair electrons from the nitrogen provides an iminium system, with the negative counter-charge on the P-carbon. 

This resonance form can then act as a nucleophile, in much the same way as an enolate anion can. However, there is a marked difference, and this is what makes enamines such useful synthetic intermediates. Generation of an enolate anion requires the treatment of a carbonyl compound with a base, sometimes a very strong base (see Section 10.2). 

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Enamines as nucleophiles react with butadiene, and a-octadienyl ketones or aldehydes are obtained after hydrolysis[57]. This is a good way of introducing an octadienyl group at the o-position of ketones or aldehydes, because butadiene does not react with ketones or aldehydes directly. The reaction of the pyrrolidine enamine of cyclohexanone gives, after hydrolysis, 2-(2,7-octadie-nyOcyclohe.xanone (58) as the main product, accompanied by a small amount of 2,6-di(2,7-octadienyl)cyclohexanone. The reaction of the optically active enamine 59 with butadiene gave 2-(2,7-octadienyl)cyclohexanone (60) in 72% ce[58]. 

Whilst the method described above appears very elegant, Weix and Hartwig expressed their discontent about the allylations of aliphatic silyl enol ethers and developed an alternative system using enamines as nucleophiles. Once the considerable initial difficulties had been overcome, these authors were able to present a procedure that gave excellent results (Scheme 9.16) [50]. 

Most enamines, unfortunately, are sensitive to hydrolysis. The parent enamine, iV,iV-dimethylvinylamine, has in fact been prepared [3], but appears to be unstable. Enamines of cyclic ketones and many aldehydes can readily be isolated, however [4-7]. The instability of enamines might at first appear to diminish the utility of enamines as nucleophiles, but actually this property can be viewed as an added benefit enamines can be readily and rapidly generated catalytically by using a suitable amine and a carbonyl compound. The condensation of aldehydes or ketones with amines initially affords an imine or iminium ion, which then rapidly loses a proton to afford the corresponding enamine (Scheme 1). 

Nitroalkenes can serve as the two-carbon fragment of a [3 + 2] cyclization involving enamines as nucleophiles (equation 86) (81LA1534). This reaction is presumably initiated by a conjugate addition of the enamine to the nitroalkene (equation 87). The most attractive formulation of the cyclization is via an intramolecular nucleophilic addition to the aci-form of the nitronate anion. This provides a reduced nitrogen substituent which could be eliminated to complete aromatization. This procedure has provided quite satisfactory yields over a range of structural types. 

This chapter introduced the use of enolates and/or enamines as nucleophiles in several reactions, including aldol reactions, Claisen condensations and Michael additions, alkylations, and acylations. We can also use LDA to generate the enolate anions and perform the same reactions, as shown here for cyclohexanone and a few specific electrophiles. Similar reactions are possible for aldehydes and esters with a-hydrogens. The synthetic versatility of this approach has made LDA a very popular and important reagent in modem synthetic organic chemistry. 

The chemical reactivity of these two substituted ethylenes is in agreement with the ideas encompassed by both the MO and resonance descriptions. Enamines, as amino-substituted alkenes are called, are vety reactive toward electrophilic species, and it is the p carbon that is the site of attack. For example, enamines are protonated on the carbon. Acrolein is an electrophilic alkene, as predicted, and the nucleophile attacks the P carbon. 

Another interesting example is provided by the phenylethynylcarbene complex 173 and its reactions with five-, six-, and seven-membered cyclic enamines 174 to form bridgehead-substituted five-, six-, and seven-membered cycloalkane-annelated ethoxycyclopentadienes with high regioselectivity under mild reaction conditions (Scheme 38) [119,120]. In these transformations the phenylethynylcarbene complex 173 acts as a C3 building block in a formal [3+2] cycloaddition. Like in the Michael additions (reaction route F in Scheme 4), the cyclic electron-rich enamines 174 as nucleophiles attack the... 

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. 

Enamine fragments present in quinolizine systems show their expected behavior as nucleophiles. For example, reaction of the indoloquinolizine derivative 78 with formaldehyde at room temperature afforded the unstable hydroxymethyl derivative 79, while reflux of 78 with formaldehyde under acidic conditions led to indole deprotection and allowed the isolation of the pentacyclic derivative 80 (Scheme 4) <2001TL7237>. 

Propadienyl phenyl sulfone can accept enamines of cyclic ketones as nucleophiles to afford fi,y-or a,/8-unsaturated ketones 193 and 194 as the major products [102],... 

Several other alkylation reactions of benzyl chloromethyl ether have been reported using phosphorus compounds as nucleophiles. Hydrolysis and alcoholysis reactions of the reagent have been investigated along with the addition of the chloroether to propylene in the presence of zinc chloride. The alkylation of enamines with benzyl bromomethyl ether has been reported. ... 

The reaction is exactly analogous to the chemical aldol reaction (also shown), but it utilizes an enamine as the nucleophile, and it can thus be achieved under typical enzymic conditions, i.e. around neutrality and at room temperature. There is one subtle difference though, in that the enzyme produces an enamine from a primary amine. We have indicated that enamine formation is a property of secondary amines, whereas primary amines react with aldehydes and ketones to form imines (see Section 7.7.1). Thus, a further property of the enzyme is to help stabilize the enamine tautomer relative to the imine. 

By using the neutral enamine as the carbon nucleophile rather than an eno-late anion, the biological system avoids the need for strongly basic reaction conditions in aldol addition. 

Most likely, the cyclization of 227 to 236 is preceded by oxidation of dialkylamine 235 into imine 238a, which then reacts in its enamine form 238b as a bifunctional C,Y-nucleophile. At first this enamine, as a C-nucleophile, attacks the C(4) atom of the pyridazine ring to produce aH-adduct 239. Further possible development of this reaction is shown in Scheme 69 (cf. Scheme 67). 

Scheme 2.1 The enamine catalytic cycle. An enamine derived from an amine- or amino acid-catalyst can react with a variety of electrophiles. The aldehyde and ketone reactants that form enamines and act as nucleophiles are often described as donors . Aldehyde and imine reactants that serve as electrophiles are described as acceptors for aldol and Mannich reactions, respectively. Ketones also serve as acceptors for aldol reactions.

Proline derivatives, such as (2S,4R)-4-hydroxyproline (2), (2S,4R)-4-tert-butoxy-proline, (2S,3S)-3-hydroxyproline [71b] and tetrazole-containing pyrrolidine 9 [75] also catalyzed the Mannich-type reactions using aldehydes as nucleophiles via enamine intermediates, and afforded the syn-isomer as the major diaster-eomer with high enantioselectivity at room temperature. On the other hand,... 

Hydrogen bond-promoted asymmetric aldol reactions and related processes represent an emerging facet of asymmetric proton-catalyzed reactions, with the first examples appearing in 2005. Nonetheless, given their importance, these reactions have been the subject of investigation in several laboratories, and numerous advances have already been recorded. The substrate scope of such reactions already encompasses the use of enamines, silyl ketene acetals and vinylogous silyl ketene acetals as nucleophiles, and nitrosobenzene and aldehydes as electrophiles. 

Alkyllithium compounds and alkali cyanides, mercaptides, and alkoxides,322,323 etc. have been used as nucleophilic reagents in reactions with the enamine salts. Nitrile groups can be removed by reduction or by treatment with acids. Treatment of cotarnine (100)... 

Because of the contribution of structures such as the one on the right to the resonance hybrid, the a-carbon of an enamine is nucleophilic. However, an enamine is a much weaker nucleophile than an enolate anion. For it to react in the SN2 reaction, the alkyl halide electrophile must be very reactive (see Table 8.1). An enamine can also be used as a nucleophile in substitution reactions with acyl chlorides. The reactive electrophiles commonly used in reactions with enamines are ... 

The array of dienophiles amenable to these hetero Diels-Alder reactions is not limited to enol ethers and enamines since allylsilanes and simple alkenes have also been successfully employed [370, 371]. More recently, it has been shown that methoxy allenes such as 4-41 undergo formation of 6H-l,2-oxazines 4-43 upon cycloaddition to nitrosoalkenes such as 4-34 and subsequent tauto-merisation of the intermediate exo-methylene compound 4-42 (Fig. 4-9) [372, 373]. In these studies, 4-43 proved to be a versatile synthetical intermediate allowing oxidative demethylation or reductive removal of the methoxy group as well as nucleophilic substitutions after the generation of an azapyrylium ion [372 - 374]. Furthermore, ring contraction reactions of these oxazines leading to pyrroles [373] and y-lactames [375] are known. 

Q Show how enols, enolate ions, and enamines act as nucleophiles. Predict the products of their reactions with halogens, alkyl halides, and other electrophiles. Show how they are useful in synthesis. 

Q Show how enols, enamines, and enolate ions act as nucleophiles. Give mecha- Problems 22-60, 61, and 65... 

The choice of the secondary amine for formation of the enamine is not completely arbitrary even though it does not end up in the final alkylated product. Simple dialkyl amines can be used but cyclic amines such as pyrrolidine, piperidine, and morpholine are popular choices as the ring structure makes both the starting amine and the enamine more nucleophilic (the alkyl groups are tied back and can t get in the way). The higher boiling points of these amines allow the enamine to be formed by heating. 

Little is known so far about a-ketoenamines, probably because they are sometimes not directly accessible from the corresponding diketones. Nevertheless, they are useful synthones, especially for heterocyclic synthesis. Compared with / -ketoenamines, the chemical behaviour of the a-keto-derivatives is somewhat different. They react as enamines, as well as a,/ -unsaturated ketones, which means that they act either as an electrophile or as a nucleophile in the -position. For example, protonation usually occurs at the fi-C atom with subsequent enolization308. Aminomethylation according to Mannich takes place in the -position as well309. The alkylation with alkyl halide, however, is reported to occur at nitrogen310,311. In addition to electrophilic and nucleophilic chemistry, a-ketoenamines are useful synthons in photochemistry and electrocyclic reactions. 

As mentioned in Section I, one of the remarkable features of 1,1-enediamines is the enhanced enaminic reactivity of the / -carbon atom. 1,1-Enediamines can serve as nucleophiles in substitution of and addition reactions to a wide variety of electron-deficient reagents. In this section we discuss mainly the alkylation, arylation and acylation reactions of 1,1-enediamines, emphasizing their synthetic utilities, especially those of secondary enediamines. 

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