Enol, specific equivalent

Disconnection of the 1,3-dlketone obviously comes next but it will be better to add an activating group to control the reaction. One possibility is to acylate specific enol equivalent (56) with acid chloride (57). 

Specific enol equivalents will be needed for both synthons (61) and (66), Since (61) is to give a double bond but (66) is to give an alcohol, the logical choices are a Wittig reagent - actually (67) - for (61) and a Reformatsky reagent for (66). The ester to aldehyde conversion (65 63) Is easiest by over-reduction and re-... 

Tiic synthesis of enone (34) requires an aldol condensation between acetone and KCHO this may not give a good yield as RCHO may prefer to condense with Itself if it has enolisable protons. The alternative disconnection (33b) avoids this problem as we can use acetoacetatc for the synthon (34) and a specific enol equivalent for (35),... 

This is a l,4 diketone and disconnection of the central bond separates the two rings. We require a specific enol equivalent lor (4) - they used activated ketone (6) - and a reagent for unnatural synthon (5) -they used a-chloroketone (7). 

One published synthesis uses a propargyl bromide for (21) and an activating group to provide a specific enol equivalent (22),... 

The disconnection strategies shown in Tables 5.2 and 5.3 suggest the acylation of a ketone, in either the a-carbanion (7) or enol (8) [or specific enol equivalent (9)] forms, as a route to a 1,3-diketone. 

Enamines are the stable products of a similar reaction between secondary amines (such as pyrrolidine or morpholine) and aldehydes and ketones.218 These vinylamines are reactive reagents of value in synthesis they function as specific enol equivalents of carbonyl compounds, readily undergoing alkylation and acylation processes (e.g. Section 5.9.2, p. 632). 

In the last chapter we used two specific enol equivalents for alkylation reactions lithium enolates and 1,3-dicarbonyl compounds. Both will help us to solve the regioselectivity problem in the... 

We need now to look at situations where both compounds might enolise and see how specific enolates can be used to control which compound does so (chemoselectivity) before looking at how we control which side of an unsymmetrical ketone forms the enolate (regioselectivity). We met two specific enol equivalents in chapter 13 (5-dicarbonyl compounds and lithium enolates and they are the keys to this section. 

Specific Enol Equivalents Good at Michael Addition... 

We met enamines as specific enol equivalents in the last chapter and they are particularly good at conjugate addition. The pyrrolidine enamine from cyclohexanone 41 adds to acrylic esters 42 in conjugate fashion and the first-formed product 43 gives the enamine 44 by proton exchange.4 Acid hydrolysis via the imine salt 45 gives the 1,5-dicarbonyl compound 46. 

Among the best specific enol equivalents for Michael addition are silyl enol ethers that are rather beyond the scope of this book but are treated in detail in Strategy and Control. So the silyl enol ether 54 of the ester 53 adds to the enone 55 with Lewis acid catalysis to give a reasonable yield of the ketoester 56 considering that two quaternary centres are joined together.6... 

Using specific enol equivalents to alkylate aldehydes and ketones... 

These side-reactions mean that aldehyde enolates are not generally useful reactive intermediates. Instead, there are a number of aldehyde enol and enolate equivalents in which the aldehyde is present only in masked form during the enolization and alkylation step. The three most important of these specific enol equivalents are ... 

You met all of these briefly in Chapter 21, and we shall discuss how to use them to alkylate aldehydes shortly. All three types of specific enol equivalent are useful not just with aldehydes, but with ketones as well, and we shall introduce each class with examples for both types of carbonyl compound. 

How would you produce specific enol equivalents at the points marked with the arrows (not necessarily starting from the simple carbonyl compound shown) ... 

Suggest how the following products might be made using enol or enolate alkylation as at least one step. Explain your choice of specific enol equivalents. 

Controlling aldol reactions with specific enol equivalents... 

In Chapter 26 we saw that the alkylation of enolates was most simply controlled by preparing a specific enol equivalent from the carbonyl compound. The same approach is the most powerful of all the ways to control the aldol reaction. The table is a reminder of some of the most useful of these specific enol equivalents. 

Specific enol equivalents are intermediates that still have the reactivity of enols or enolates but are stable enough to be prepared in good yield from the carbonyl compound. That was all we needed to know in Chapter 26. Now we know that... 

Sensible choice of an appropriate specific enol equivalent will allow almost any aldol reaction to be performed successfully. The first two compounds in our list, the silyl enol ethers and the lithium enolates, have a specially wide application and we should look first at the way these work. As the table suggests, silyl enol ethers are more like enols they are nonbasic and not very reactive. Lithium enolates are more like enolate anions they are basic and reactive. Each is appropriate in different circumstances. 

This reaction works well even if the electrophilic partner is an enolizable aldehyde. In this example, an unsymmetrical ketone (blocked on one side by an aromatic ring) as the enol partner reacts in excellent yield with a very enolizable aldehyde. This is the first complete aldol reaction we have shown you using a specific enol equivalent notice the important point that it is done in two steps— first, form the specific enol equivalent (here, the lithium enolate) then add the electrophile. Contrast the crossed aldols earlier in the chapter, where enolizable component, base, and electrophile were all mixed together in one step. 

The use of silyl enol ethers can be illustrated in a synthesis of manicone, a conjugated enone that ants use to leave a trail to a food source. It can be made by an aldol reaction between the pentan-3-one (as the enol component) and 2-methylbutanal (as the electrophile). Both partners are enolizable so we shall need to form a specific enol equivalent from the ketone. The silyl enol ether works well. 

When the Wittig reaction was introduced (Chapter 14) we saw it simply as an alkene synthesis. Now if we look at one group of Wittig reagents, those derived from a-halo-carbonyl compounds, we can see that they behave as specific enol equivalents in making unsaturated carbonyl compounds. 

The conjugated ylides derived from aldehydes, ketones, and esters are all sufficiently stable to be commercially available as the ylids—one of the few examples of specific enol equivalents that you can actually buy. The ylid corresponding to the enolate of acetaldehyde is a solid, m.p. 185-188 °C that reacts well with other aldehydes, even if they are enolizable. 

Though these are the oldest of the specific enol equivalents, they are still widely used because they need no special conditions—no low temperatures or strictly anhydrous solvents. The two most important are derived from mal-onic acid and ethyl acetoacetate. 

We have now completed our survey of the most important types of aldol reaction and of the varieties of specific enol equivalents available. We shall now move on to look at carbonyl compounds type by type, and consider the best options for making specific enol equivalents of each. 

Specific enol equivalents for carboxylic acid derivatives... 

For the remainder of this section we shall look at how to make specific enol equivalents of the remaining carboxylic acid derivatives. 

Among the enolates of carboxylic acid derivatives, esters are the most widely used. Ester enolates cannot be used in crossed aldols with aldehydes because the aldehyde is both more enolizable and more electrophilic than the ester. It will just condense with itself and ignore the ester. The same is true for ketones. A specific enol equivalent for the ester will therefore be needed for a successful ester aldol reaction. 

Other useful specific enol equivalents of aldehydes and ketones are enamines and aza-enolates, which you saw in use in alkylation reactions in Chapter 26. Aza-enolates—the lithium enolates of imines—derived from aldehydes are useful too in aldol reactions. 

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