Enamines with electrophilic alkenes

Enamines also react with electrophilic alkenes to give conjugate addition products. The addition reactions of enamines of cyclohexanones show a strong preference for attack from the axial direction.319 This is anticipated on stereoelectronic grounds because the tt orbital of the enamine is the site of nucleophilicity. 

Enamines also react with electrophilic alkenes. This aspect of their chemistry will be described in Section 1.10. 

Enamines represent nucleophilic alkenes which undergo cycloaddition reactions readily with electrophilic alkenes. For example, acrylonitrile (5) reacts with cyclic enamines 10 to give bicyclic aminocyclobutanenitrilcs 11, albeit in poor yields.29... 

As pointed out by Stork and coworkers in their definitive 1963 paper3, the reaction with electrophilic alkenes is especially successful since reaction at nitrogen is reversible. Reaction at the /2-carbon is (usually) rendered irreversible by, in the case of cyclohexanone enamines, internal proton transfer of the axial C-/2 proton to the anionic centre of the initially formed zwitterionic intermediate (34), under conditions of stereoelectronic control (Scheme 22). When this intramolecular proton transfer cannot occur in aprotic solvents, or when the product produced in protic solvents is a stronger carbon acid than adduct 35 (i.e. when Z = COR, N02), then carbon alkylation is also reversible and surprising changes in the regioselectivity of reaction may be observed (vide infra see also Section VI.D and Chapter 26). Cyclobutanes (36) and, in the case of a,/ -unsaturated... 

Conceptually similar a,a -annulations of ketone enamines have also been carried out with electrophilic alkenes containing a reactive allylic halogen, such as ethyl a-bromo-methylacrylate or dimethyl y-bromomesaconate318-320 (Scheme 156). An elegant one-pot synthesis of the adamantane ring system involving sequential double Stork and Dieckmann reactions has been developed by Stetter and Thomas321 (Scheme 157). Reaction of the bis-enamine 154 with ethyl a-bromomethylacrylate leads to the pentacy-clic system 155322 (Scheme 158). 

Enamines undergo [4 + 2]cycloaddition with electrophilic alkenes such as ethyl sorbate327, methyl 2,4-pentadienoate3272,328, penta-2,4-dienol329, hexa-3,5-dien-2-... 

The alkylation of acyclic imines with electrophilic alkenes such as acrylonitrile, methyl acrylate or phenyl vinyl sulphone is also sensitive to steric effects and again, as a consequence, only mono-alkylation occurs398. The regioselectivity of the reaction in methanol varied from 100% attack at the more substituted a-position to 70% attack at the less substituted a -position depending upon the steric inhibition manifested and the stabilization of the competing secondary enamine tautomers (vide infra) (Scheme 204). In contrast, the reaction of butanone and other methyl ketone imines with phenyl vinyl ketone occurs twice at the more substituted a-position but this is then followed by a double cyclization process (Scheme 205). Four carbon-carbon bonds are formed sequentially in this one-pot synthesis of the bicyclo[2.2.2]octanone 205 from acyclic precursors399,400. 

C-Alkylations of hindered aldehyde enamines can be effected with a variety of alkylating agents, but only allylic and benzylic reagents are useful for alkylations of unhindered systems.Acyclic, homoan-nular and heteroannular dienamines undergo alkylation primarily at the a-positions. ° As discussed above, reactions of enamines with electrophiles containing sp -hybridized carbon atoms have numerous limitations. On the other hand, enamine reactions with electrophilic alkenes are highly useful and have received wide coverage in the literature. 

The mechanism of the alkylation of imines with electrophilic alkenes has been discussed by D Angelo and coworkers S who conclude that reaction occurs via an aza-ene reaction-like transition state 206 involving concerted proton transfer from the nitrogen and carbon-carbon bond formation (Scheme 206). ITiey further propose that the remarkable regiocontrol observed in these reactions originates from this crucial internal proton transfer which would not be possible in a conformation such as 207 of the less substituted enamine tautomer, since the N—H bond would be anti to the enamine double bond. However, although this seems probable, it is by no means proven. Inconsistencies in the argument and the evidence presented cast some doubt on the validity of these conclusions. For example ... 

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. 

The reactions of electrophilic alkenes (alkenes attached to electron-withdrawing groups) with enamines produce one or more of the following products simple alkylation (2), 1,2 cycloaddition (3), and 1,4 cycloaddition (4). Competition with C alkylation by N alkylation is inconsequential and therefore will be largely ignored (5,7). A stepwise ionic mechanism leading to these products necessarily involves the formation of a zwitterion intermediate (1) as the first step, which is then followed either by one of the... 

Olefins conjugated with electron-withdrawing groups other than a carbonyl group undergo reactions with enamines in a manner similar to the carbonyl-conjugated electrophilic alkenes described above. Namely, they condense with an enamine to form a zwitterion intermediate from which either 1,2 cycloaddition to form a cyclobutane ring or simple alkylation can take place. 

In cyclopropanations with electrophilic carbene complexes, yields of cyclopropanes tend to improve with increasing electron density of the alkene. As illustrated by the examples in Table 3.5, cyclopropanations of enol ethers with aryldiazomethanes often proceed in high yields. Simple alkyl-substituted olefins are, however, more difficult to cyclopropanate with diazoalkanes. A few examples of the cyclopropanation of enamines with diazoalkanes have been reported [650]. 

For more reactive electrophilic alkenes possessing two or more electron-withdrawing groups, cycloadditions with enamines occur under mild conditions. The cycloadditions of A,A -dimethyl-2-methylprop-1-enamine (12) with a series of electrophilic alkenes 13 proceed at temperatures ranging from — 30 °C to room temperature in short reaction times to give good to very good yields of the aminocyclobutanes 14.30... 

All the substrates A E introduced here are alkenes that are electron-rich. This is why they react with electrophiles. Enols (A), enol ethers (C), silyl enol ethers (D) and silylketene acetals (E) react electrophiles to form oxocarbenium or carboxonium ions, whereas the reaction of enamines (B) with electrophiles gives iminium ions ... 

Similarly, the enamine of a 2-substituted cyclohexanone is alkylated by electrophilic alkenes such as acrylonitrile or methyl acrylate at the exposition in methanol or acetonitrile. However, prolonged reaction time (66 h) of the pyrrolidine enamine of 2-methylcyclohexanone with these reagents in dioxane or benzene under reflux gives a 1 1 mixture of 2,2- and 2,6-disubstituted cyclohexanones (38 and 39)82>83 (Scheme 23). 

Evidence for the two-step nature of the dihydropyran formation follows from the observation that both cis- and fraws-dibenzoylethene gave the same dihydropyran96, under conditions where cis-trans isomerism of the electrophilic alkene did not occur. On heating, the dihydropyrans rearrange into a mixture of the corresponding alkylated enamines (44 and 45) (Scheme 29). This is kinetically rather than thermodynamically controlled, since the equilibrium composition was obtained only after treatment with acid96, and can therefore be regarded as irreversible in an aprotic solvent (benzene) at 80°C. 

The reaction of enamines and imines with acrylamide results in aza-annulation120,121. Other electrophilic alkenes which have been used to alkylate enamines and the products used in hetero- or carbocyclic synthesis include ethyl / -nitroacrylate122, where reaction occurs beta to the nitro not the ester group, 2-(phenylseleno)prop-2-enenitrile [CH2 = C(SePh)CN]123,124, phenyl a-phenylselenovinyl sulphone [CH2 = C(SePh)-S02Ph]124 and phenyl a-bromovinyl sulphone124. An electrophilic allene, phenylsulpho-nylpropadiene, has also been used to alkylate enamines125 (Scheme 44). 

Cyclopropanes have also been obtained by reaction of enamines with a-chloro electrophilic alkenes. After Michael addition the chlorine undergoes nucleophilic displacement by the regenerated enamine or enolate anion260,261 (Scheme 112). Bicy-clo[ 1.1.0] butanes may be obtained by cycloaddition of trimethyl ethylenetricarboxylate followed by a base catalysed displacement of the amine moiety262 (Scheme 113). 

Four-membered carbocyclic ring systems are commonly formed by cycloaddition of electrophilic alkenes, ketenes and arynes to enamines. Since cycloaddition reactions of enamines are dealt with in Chapter 18 these reactions will only be mentioned briefly here. 

Diethyl azodicarboxylate (DAD) behaves like a reactive electrophilic alkene and attack on a substituted cyclohexanone enamine can occur from an axial or equatorial direction depending on the steric effects in the transition state. For example, DAD reacts with 159 to give 160 by equatorial attack, together with 161 (ratio 1 9), whereas the... 

The morpholine enamine of fra/i.s-2-decalone exists as a 1 4 mixture of A1- and A2-isomers DAD reacts with the former by equatorial attack and the latter by axial attack351 (Scheme 177). In contrast, less electrophilic alkenes, such as / -nitrostyrene and phenyl vinyl ketone, react only with the A2-isomer at C-3 by axial attack (see Section III.B), unless sterically impeded. 

A further difference to electrophilic alkenes shown by DAD and other diimides is that tertiary amines, such as A-cyclohexylpyrrolidine (167), are dehydrogenated to the enamine. Further reaction then occurs to give the product of 2,6-disubstitution (168)352. Diacyl diimides, such as dibenzoyldiimide (DBD), are even more remarkable. The action of DBD on 167 at room temperature results in dehydrogenation of the pyrrolidine ring and reaction with a further two equivalents of DBD to give 169353 (Scheme 178). 

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