Enolates reactivity towards electrophiles

The enolate anions are more reactive towards electrophiles when they are associated with non-coordinating quaternary ammonium cations than when they are associated with lithium cations. Thus, as illustrated in Equations Si3.4 and Si3.5, quaternary ammonium derivatives are preferred as counterions for kinetic enolates in order to prevent any isomerization to the thermodynamic enolate occurring before reaction with the added electrophile proceeds. 

Veya and coworkers found that for M = K the enolates [Ph2PCH=(Ph)—0] M+ and [Ph2PCH=C(OEt)—0] M+ should be much less reactive toward electrophiles (e.g. CO2, activated afkynes) than for M = Pd[(NMe2CHPh) ]. These authors performed ab initio calculations on both free phosphine enolate anion and when M = Li or Na, to rationalize their reactivity toward electrophiles as a function of their electronic properties. 

There is another feature of silyl enolates worthy of special comment. Silyl enolates are less reactive toward electrophiles than their respective lithium... 

Enolate ions are more useful than enols for two reasons. First, pure enols can t normally be isolated. They are usually generated only as short-lived intermediates in low concentration. By contrast, stable solutions of pure enolate ions are easily prepared from most carbonyl compounds by reaction wilh a strong base. Second and more important, enolate ions are much more reactive than enols and undergo many reactions that enols don t. Whereas enols are neutral, enolate ions are negatively cheirged, making them much better nucleophiles. Thus, the a carbon atom of an enolate ion is highly reactive toward electrophiles. An electrostatic potential map of acetone enolate ion, for instance, shows the electron-rich character (red) of the a carbon. 

The use of 0-metallation of alcohols or enols to enhance their reactivity towards electrophiles, such as aldehydes or alkyl or acyl halides has been reported by Davies.The reaction of triorganotin alkoxides with other polar multiply-bonded acceptors was also reported (Scheme 6.3.8). 

Enolates are much more reactive towards electrophiles than enols because they are negatively charged. Enolates can react with electrophiles on oxygen, although reaction on carbon is more commonly observed. 

The direct grafting of functional gronps or moieties onto PCL is another path toward fnnctionalized PCL. Using a strong base, a proton can be abstracted from the aliphatic polymer backbone and a wide range of fnnctional gronps can be attached. Using lithium diisopropylamide, enolates are formed that are reactive towards electrophiles such as carbon dioxide and benzaldehyde, thns precnrsors of acid and hydroxyl moieties [74]. 

With ketone 271 in hand, focus turned to construction of the furoindole scaffold via a Fischer indolization. The lithium enolate of ketone 271 was generated in situ using lithium hexamethyldisilazide in a mixture of l,3-dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone (DMPU) and THF (Scheme 36). Although this enolate is noted not to be very reactive toward electrophiles, treatment with allyl iodide affected a facile alkylation to provide ketone 272. 

In tropolones electronic interaction between the functional groups is facilitated by the planar geometry of the molecule. Both tropolones and B-diketones (in their enol form) are examples of push-pull alkenes and contain enol moieties which lead to ready reactivity towards electrophiles at the 3-, 5- and 7-positions of tropolones as at the 2-carbon atom of 1,3-diketones, which in the latter case had been recognised many years earlier. 

Control of the stereoselectivity in nucleophilic additions to the carbonyl group. Facial selectivity. Felkin Anh s and Cram s models. Reactivity of TMS enol ethers towards electrophiles. 

The SAMP/RAMP Method As early as 1976, azaenolates derived from A,A-dialkyl hydrazones were studied as an alternative to direct ketone and aldehyde enolate alkylations. These species were found to exhibit higher reactivity toward electrophiles, as well as better regioselectivity for C-alkylation than their parent carbonyl compounds. A,A-diaIkyl hydrazones are stable and are relatively easy to prepare, making them appealing from a practical point of view in comparison with imines and enamines, which can be difficult to form quantitatively and are hydrolytically unstable. Given these desirable attributes, Enders undertook the development of chiral nonrace-mic A,A-diaIkyl hydrazine auxiliaries for the asymmetric a-alkylation of ketones. The result of his efforts were (5)-and (R)-l-amino-2-methoxypyrrohdine hydrazine (1 and 2, respectively), now commonly known as the SAMP and RAMP auxiliaries, respectively (Figure 7.1). Over the years, the SAMP/RAMP method has come to be considered the state-of-the-art approach to asymmetric ketone... 

As discussed in Section 4.01.5.2, hydroxyl derivatives of azoles (e.g. 463, 465, 467) are tautomeric with either or both of (i) aromatic carbonyl forms (e.g. 464,468) (as in pyridones), and (ii) alternative non-aromatic carbonyl forms (e.g. 466, 469). In the hydroxy enolic form (e.g. 463, 465, 467) the reactivity of these compounds toward electrophilic reagents is greater than that of the parent heterocycles these are analogs of phenol. 

Entry 9 of Scheme 2.1 is an example of application of these conditions. Tin(II) enolates prepared in this way also show good reactivity toward ketones as the electrophilic component. 

Erlenmeyer was first to consider ends as hypothetical primary intermediates in a paper published in 1880 on the dehydration of glycols.1 Ketones are inert towards electrophilic reagents, in contrast to their highly reactive end tautomers. However, the equilibrium concentrations of simple ends are generally quite low. That of 2-propenol, for example, amounts to only a few parts per billion in aqueous solutions of acetone. Nevertheless, many important reactions of ketones proceed via the more reactive ends, and enolization is then generally rate-determining. Such a mechanism was put forth in 1905 by Lapworth,2 who showed that the bromination rate of acetone in aqueous acid was independent of bromine concentration and concluded that the reaction is initiated by acid-catalyzed enolization, followed by fast trapping of the end by bromine (Scheme 1). This was the first time that a mechanistic hypothesis was put forth on the basis of an observed rate law. More recent work... 

Silyl enol ethers are quite reactive towards IOB-boron trifluoride (or tetrafluoroboric acid) and can be considered as valuable starting materials for several reactions of synthetic importance. Of special interest is their use for carbon-carbon bond formation 1,4-diketones and unsaturated ketones are the products of such reactions further, they can be transformed to oc-hydroxy, methoxy or trifyloxy ketones. With tetrafluoroboric acid IOB forms a yellow solution containing the highly electrophilic Phi+ OH BF4 , stable up to 0°C. This species reacts readily with silyl ethers of several ketones, notably acetophenones, at —78°C, forming an unstable iodonium ion (ArCOCH2I+ Ph) which with another silyl ether affords 1,4-diketones. 

Phenol complexes of [Os] display pronounced reactivity toward Michael acceptors under very mild conditions. The reactivity is due, in part, to the acidity of the hydroxyl proton, which can be easily removed to generate an extended enolate. Reactions of [Os]-phenol complexes are therefore typically catalyzed using amine bases rather than Lewis acids. The regio-chemistry of addition to C4-substituted phenol complexes is dependent upon the reaction conditions. Reactions that proceed under kinetic control typically lead to addition of the electrophile at C4. In reactions that are under thermodynamic control, the electrophile is added at C2. These C2-selective reactions have, in some cases, allowed the isolation of o-quinone methide complexes. As with other [Os] systems, electrophilic additions to phenol complexes occur anti to the face involved in metal coordination. 

Electrophilic reactivity Derivative Structure Reactivity towards enolate formation... 

As emphasized in Section IV of this chapter, the lithiotropy is of much consequence in the reactivity of enolates, the O and C sites competing toward electrophiles. This problem has been examined recently by Meneses and coworkers202, who described a local hardness parameter that can be used as a selectivity index, in particular for a set of ketone lithium enolates. 

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