Enols electrophilic attack

Enol ethers are readily attacked in buffered medium by electrophilic reagents such as halogens, A -haloamides, perchloryl fluoride and organic peracids to give a-substituted ketones. Similarly, electrophilic attack on... 

OL Halogenation (Sections 18.2 and 18.3) Halogens react with aldehydes and ketones by substitution an a hydrogen is replaced by a halogen. Reaction occurs by electrophilic attack of the halogen on the carbon-carbon double bond of the enol form of the aldehyde or ketone. An acid catalyst increases the rate of enolization, which is the ratedetermining step. 

HOMO of acetone enolate reveals most likely site of electrophilic attack. 

HOMO map for enolate B reveals preferred stereochemistry of electrophilic attack. 

The few exceptions to this general rule arise when the a-carbon carries a substituent that can stabilize carbonium-ion development well, such as oxygen or sulphur. For example, 1-trimethylsilyl trimethylsilyl enol ethers give products (72) derived from electrophilic attack at the /J-carbon, and the vinylsilane (1) reacts with a/3-unsaturated acid chlorides in a Nazarov cyclization (13) to give cyclopentenones such as (2) the isomeric vinylsilane (3), in which the directing effects are additive, gives the cyclopentenone (4) ... 

For those substrates more susceptible to nucleophilic attack (e.g., polyhalo alkenes and alkenes of the type C=C—Z), it is better to carry out the reaction in basic solution, where the attacking species is RO . The reactions with C=C—Z are of the Michael type, and OR goes to the side away from the Z. Since triple bonds are more susceptible to nucleophilic attack than double bonds, it might be expected that bases would catalyze addition to triple bonds particularly well. This is the case, and enol ethers and acetals can be produced by this reaction. Because enol ethers are more susceptible than triple bonds to electrophilic attack, the addition of alcohols to enol ethers can also be catalyzed by acids. " One utilization of this reaction involves the compound dihydropyran... 

Although the reaction of ketones and other carbonyl compounds with electrophiles such as bromine leads to substitution rather than addition, the mechanism of the reaction is closely related to electrophilic additions to alkenes. An enol, enolate, or enolate equivalent derived from the carbonyl compound is the nucleophile, and the electrophilic attack by the halogen is analogous to that on alkenes. The reaction is completed by restoration of the carbonyl bond, rather than by addition of a nucleophile. The acid- and base-catalyzed halogenation of ketones, which is discussed briefly in Section 6.4 of Part A, provide the most-studied examples of the reaction from a mechanistic perspective. 

Silyl enol ethers and silyl ketene acetals also offer both enhanced reactivity and a favorable termination step. Electrophilic attack is followed by desilylation to give an a-substituted carbonyl compound. The carbocations can be generated from tertiary chlorides and a Lewis acid, such as TiCl4. This reaction provides a method for introducing tertiary alkyl groups a to a carbonyl, a transformation that cannot be achieved by base-catalyzed alkylation because of the strong tendency for tertiary halides to undergo elimination. 

The oxidation is regarded as taking place by an electrophilic attack of selenium dioxide (or selenous acid, H2Se03, the hydrate) on the enol of the ketone or aldehyde. This is followed by hydrolytic elimination of the selenium.258... 

In reactions with azides, ketones are directly converted to 5-hydroxytriazolines. Ketone enolate 247, generated by treatment of norbornanone 246 with LDA at 0°C, adds readily to azides to provide hydroxytriazolines 248 in 67-93% yield. Interestingly, l-azido-3-iodopropane subjected to the reaction with enolate 247 gives tetracyclic triazoline derivative 251 in 94% yield. The reaction starts from an electrophilic attack of the azide on the ketone a-carbon atom. The following nucleophilic attack on the carbonyl group in intermediate 249 results in triazoline 250. The process is completed by nucleophilic substitution of the iodine atom to form the tetrahydrooxazine ring of product 251 (Scheme 35) <2004JOC1720>. 

These reactions were proposed to proceed via electrophilic attack on the enol by the SN reagents at N followed by cyclization either via a second enol as in compound 151 or by cyclization onto the more reactive carbonyl <1997J(P1)2831>. Unsymmetrical 1,3-diketones can give a mixture of regioisomers if both carbonyls have similar reactivities however, aroylacetones react regiospecifically to afford only the 3-aroyl-4-alkyl-l,2,5-thiadiazoles 154 (R = Me). 

Despite the fact that the electrochemical oxidation of most of the nonconjugated dienes generally does not give products which result from interaction of the double bonds with one another, the anodic oxidation l-acetoxy-l,6-heptadienes gives intramolecularly cyclized products, that is, the cyclohexenyl ketones (equation 15)13. The cyclization takes place through the electrophilic attack of the cation generated from enol ester moiety to the double bond. 

Six-Membered Ring (endo-Cyclic). All the previous discussion of stereo-attack is based on steric hindrance, but in the case of a six-membered ring (endo-cyclic) enolate, the direction is affected simultaneously by stereo-electronic effects (Scheme 2-4).10 In the transition state, the attacking electrophiles must obey the principle of maximum overlap of participating orbitals by perpendicularly approaching the plane of atoms that constitute the enolate functional group. Electrophile attacks take place on the two diastereotopic... 

The first step is protonation. Because both C3 and C4 need to pick up protons, we protonate on C4. At this point, there s not much we can do except allow H20 to add to the carbocation, even though this is not a bond that is in our list of bonds that need to be made we will need to cleave it later. Addition of 08 to C5, H+ transfer from 08 to 06, and cleavage of the C5-06 bond follow. At this point we still need to make the C1-C5 bond. C5 is clearly electrophilic, so Cl needs to be made nucleophilic. Proton transfer from 08 to C3 and another H+ transfer from Cl to 08 gives the Cl enol, which attacks the C5 carbocation. Another H+ transfer from Cl to 08 is followed by cleavage of the 08-C5 bond, and loss of H+ gives the product. 

The utility of chiral oxazoline enolates in asymmetric synthesis has elegantly been demonstrated by Myers (106,120). The stereoselective aldol condensations of these enolates have been examined in a hmited number of cases (eq. [107]) (32,121). Assuming that the enolate formed has the geometry indicated in 164 (120b), the diastereoselection observed for both the aldol condensation and the previously reported alkylations favors electrophile attack on the Re face as indicated. In contrast, the unsubstituted enolate 163b exhibits significantly poorer diastereoface selection with a range of aldehydes (eq. [108]) (121). 

As shown in Scheme 9.31, the (S)-enolate (100a), from Evans reagent 100. reacts on its Re face if the metal is not coordinated to the oxazolidone carbonyl group at the time of electrophilic attack, which is the normal situation in an uncatalysed boron enolate aldol reaction (see Scheme 9.14) and on the Si face if the metal is coordinated to the oxazolidone carbonyl group (lOOb), which is the normal situation in enolate alkylation (see 9.3.2). 

Again, the exclusive formation of six-membered rings indicates that the cyclization takes place by the electrophilic attack of a cationic center, generated from the enol ester moiety to the olefinic double bond. The eventually conceivable oxidation of the terminal double bond seems to be negligible under the reaction conditions since the halve-wave oxidation potentials E1/2 of enol acetates are + 1.44 to - - 2.09 V vs. SCE in acetonitrile while those of 1-alkenes are + 2.70 to -1- 2.90 V vs. Ag/0.01 N AgC104 in acetonitrile and the cyclization reactions are carried out at anodic potentials of mainly 1.8 to 2.0 V vs. SCE. 

The possible pathways for the transformations 323 -> 324 and 323 - 325 are outlined in Scheme 84. The first step that is common to these reactions involves the electrophilic attack of the I(III) species on the enol form of 323 at the face of the molecule anti to the C(2)-aryl ring to provide intermediate 328. Routes (a) and (a ) involving a 1,2-aryl shift lead to isoflavones 324. Route (b), involving Sn2 attack of X /XH at the C(3)-position of intermediate 328, leads to 325 via 329. The nucleophilicity of X XH plays a deciding role in affecting the course of the reaction. 

The use of TMOF as a solvent provides strong acetalizing conditions (323 330). This allows the generation of enol ether 331, which on electrophilic attack of hypervalent iodine species [PhI(OMe)2] (83IC1563) gives intermediate 332. Nucleophilic attack of the solvent at the C(4)-position of 332, followed by migration of ring A, results in the formation of 326. The minor product 327 is resulted by a Sn2 attack of methanol at the C(3)-position of 333 (Scheme 85). 

A detailed examination of OSO4 reactions with A -steroids has been reported." The A-ring conformation of the reactant or derived complex is important in determining the stereoselectivity of these reactions, and the major role of the proximate substituents is to anchor the appropriate conformation favouring a- or /3-attack. Studies on the stereochemistry of electrophilic attack on cholest-5-en-3-one continue." As with bromine chloride," appreciable /3-attack occurs and the 5/3,6j8-epoxide was isolated along with the previously reported 5a,6a-epoxide and the Baeyer-Villiger product, the A-homo-enol lactone (58). Base-catalysed... 

In acidic solution, dihydrothiazin-3-ones are in equilibrium with their enol form and susceptible to electrophilic attack at the 2-carbon. They can be oxidized at this site with peracids or diacyl peroxides (Scheme 25) <19828312, 1982S424>. 

The enolate generated by reaction of lactone 88 with lithium diisopropylamide (LDA) is quenched with an excess of methyl iodide to give methyl lactone 89 in excellent yield. As expected, the electrophilic attack is stereoselective for the less sterically hindered convex face of the lactone enolate, giving the product with the desired 7iJ-stereochemistry with greater than 95 5 selectivity (Equation 22) <1997TL3817>. 

The high diastereoselectivity can be explained by looking at the conformations of 5 with either a pseudoaxial methyl group 5a or a pseudoaxial trialkylsiloxypropyl group 5b which shield the enolate from attack of an electrophile on the same side. 

Rotation around the C-N bond in the chelated enolate is hindered. Thus, electrophilic attack will occur preferentially from one side. If, however, rotation around the C-N bond is more or less free, as is the case with nonchelated intermediates, then the electrophilic attack may be less selective. 

Treatment of the pyrrolidone mixture 5 with 2.1 equivalents of lithium diisopropylamide at — 78 °C for 1 hour, and then — 25 °C for 1 hour, yields the dianionic enolate. Alkylation at -117 °C or - 78 °C then provides a 50-80% yield of the (3S)-alkylated 3,4-tran.v-product as a 85 15 mixture of the 5-epimers19,20. No trace of the 3,4-a.s-product could be detected by NMR. The electrophile attacks from the side opposite to the alkoxide group. Evidently, in this case, the stereogenic center in the 5-position has no influence on the stereoselectivity. 

Since the chirality of the center undergoing electrophilic attack is destroyed on enolate formation, the enantiomerically pure civ-isomer of the 5-alkyl-2-/cr -butyl-4-imidazolidinone 8, after alkylation and hydrolysis, gives the enantiomer of the a-alkyl-a-amino acid obtained on alkylation of the trans-isomer 8 provided that the cis- and trans-isomers have been prepared from the same enantiomer of the starting amino acid3. 

The high diastereoselectivity observed with benzylic halides has been explained by postulating an interaction between the aromatic ring of the halide and the conjugated double bonds of the enolate intermediate. One face of the enolate is shielded by the benzene ring of the phenyl-ethanamine moiety, thus hindering electrophilic attack. 

The opportunity for chelation in the various enolate intermediates offers a possible explanation for the observed diastereoselectivities. In the dianions derived from l-acyl-2-pyrrolidinemethanols strong chelation of both of the lithium cations should lead to a rigid enolate structure 9. It is reasonable to assume that the pyrrolidine ring is locked in one conformation. Since, according to models, it is difficult to attribute the observed high diastereoselectivity to steric hindrance, it is probable that the lone pair on the nitrogen directs the facial selectivity of electrophilic attack (see Section 1.1.1.3.3.1.) to one side of the enolate a-carbon. 

Because enol ethers are more susceptible than triple bonds to electrophilic attack, the addition of alcohols to enol ethers can also be catalyzed by acids.170 One utilization of this reaction involves the compound dihydropyran (28), which is often used to protect the OH... 

---