Disconnections carbonyl compounds

Before we complete the disconnections of carbonyl compounds we shall look at some aspects of control in synthesis as a break from the systematic analysis. 

So we can disconnect any a,p-imsaturated carbonyl compound along the double bond, writing CH2 at one end and C=0 at tbe other. 

One extra disconnection is all we need to cope with misaturated heterocycles. If a nitrogen atom is joined to a double bond in a ring, we have a cyclic enamine. This is made from an amine and a carbonyl compound in the same way as ordinary enamines ... 

Analysis Another lactone FGl reveals the true TM (A). Our normal discormection a of an a,p-unsaturated carbonyl compound gives us the 1,5-dicarbonyl compound (B) and the ketone (C) clearly derived from phenol. Alternatively we could disconnect bond b to the keto-ester (D) with the further discormection shown ... 

To identify the carbonyl compound and the ylide required to produce a given alkene mentally disconnect the double bond so that one of its carbons is derived from a car bonyl group and the other is derived from an ylide Taking styrene as a representative example we see that two such disconnections are possible either benzaldehyde or formaldehyde is an appropriate precursor... 

Problem Make the first disconnection to show how these molecules might be made by organo-copper addition to suitable carbonyl compounds. 

Two-Group Disconnections II 1,3-Difunctionalised Compounds and (X, d-Unsaturated Carbonyl Compounds... 

Write disconnections and starting materials forthi.> i-hydroxy carbonyl compounds. 

The most important of these three types of target innlecule is the a, S-unsaturated carbonyl compound. Disconnect TMs (10) and (11) and provide starting materials. 

Example Compound (21) may not look like a Robinson annelation product, but it is certainly an enone so a,B disconnection gives a 1,5-di-carbonyl compound A reverse Michael reaction disconnecting the ring from the chain gives enone (22),... 

In connection with monofunctionalised molecules we have already referred to a "plausible disconnection" according to which an alcohol can be directly "disconnected" at the a-position, in such a manner that an epoxide rather than a carbonyl compound results, as for example in the case of the tertiary alcohol 14 ... 

With respect to the above-mentioned unsaturated carbonyl compounds with a double bond and a carbonyl group separated by three carbon atoms (14), it can be stated here that they may be disconnected to an alkyl vinyl ketone and an allylic anion (Scheme 7.5), through an oxy-Cope rearrangement (C/. Scheme 5.22). 

By bond polarity and resonance, the carbonyl carbon and a carbon (i to the carbonyl carbon can be utilized as electrophilic centers—die carbonyl group by direct nucleophilic addition and die /3 carbon by Michael addition to an a,/3-unsaturated ketone. By resonance interaction, the a position in carbonyl compounds and y positions in o, /3-unsaturated carbonyl compounds can be converted to nucleophilic centers by proton removal. These normal polarities are used frequently in retrosynthetic planning as points of disconnection to establish potential bond-forming steps using carbonyl groups. 

A retrosynthetic analysis for a target molecule of either a primary or secondary amine is therefore a two-stage process first an FGI to reveal an imine, and then a disconnection to ammonia (or primary amine) and the carbonyl compound. 

The synthetic method (a) is the regioselective reduction of an a,/ -unsaturated aldehyde or ketone (Section 5.18.2, p. 798), which is most conveniently effected by the Meerwein-Ponndorf-Verley procedure (Section 5.4.1, p. 520). The further disconnection shown of the a, -carbonyl compound is a retro-aldol condensation (Section 5.18.2, p. 799) however it should be emphasised that other routes to the unsaturated carbonyl compound, such as the Horner-Emmons reaction (Section 5.18.2, p. 799), may also be feasible. 

A retrosynthetic analysis of an a,/J-unsaturated aldehyde or ketone involves an initial functional group interconversion into a /1-hydroxycarbonyl compound, followed by a disconnection into the carbocation (12) and the carbanion (13) synthons. The reagent equivalents of these two synthons are the corresponding carbonyl compounds. 

In these problems the principles of retrosynthetic analysis are applied. The alkyl groups attached to the carbon that bears the hydroxyl group are mentally disconnected to reveal the Grignard reagent and carbonyl compound. 

The disconnection 47 gives a different synthon 48 at the carbonyl oxidation level and the best reagents are the a-halo carbonyl compounds 49. At first this looks like a one-group disconnection but there are two reasons why it isn t. The presence of the carbonyl group makes the Sn2 displacement of halide enormously faster and the a-halo carbonyl compounds 49 are made from the ketone 51 by acid-catalysed halogenation of the enol 50. 

Compounds like the ester 56 were briefly mentioned in chapter 4 and we can now show how they can be made by a two-group disconnection. The electrophile will be the a-halo carbonyl compound 57 and the nucleophile the anion of a carboxylic acid. 

The label 1,1-diX may look strange but all it means is that the two functional groups are joined to the same carbon atom. You already know how to make acetals 68 you combine an aldehyde 67 with an alcohol, say methanol, in acidic solution. The disconnection 68a is therefore of both C-0 bonds. This reveals a valuable truth two heteroatoms joined to the same carbon atom are at the carbonyl oxidation level (two C-0 bonds to the same C atom in both 67 and 68) and the TM is probably made from a carbonyl compound. 

A preliminary FGI is needed before we apply the C-N disconnection. Amine 17 could be made from amide 18 or imine 21 and hence from two different primary amines 20 or 22 and two different carbonyl compounds 19 or 23. These methods are very versatile. 

For compounds with two heteroatoms joined to the same carbon, we used a 1,1-diX disconnection I removing one heteroatom to reveal a carbonyl compound, here an aldehyde, and a heteroatom nucleophile 2. Replacing the heteroatom by R2, we disconnect in the same way to reveal the same aldehyde and some nucleophilic carbon reagent 4, probably R2Li or R2MgBr. 

Acids can also be made by the oxidation of alcohols and acid derivatives are available from the acids via the acid chloride. Since acids can also be reduced to alcohols, there is a great deal of interdependence in all these methods. The synthesis of carbonyl compounds by one-group C-C disconnections is discussed more fully in chapter 13. 

In chapter 10 we compared C-C disconnections with related two-group C-X disconnections, mainly at the alcohol oxidation level. In this chapter we deal more fully with carbonyl compounds, chiefly aldehydes and ketones, by two related disconnections. We start by comparing the acylation of heteroatoms by acid derivatives such as esters (a 1,1-diX disconnection 1 that can also be described as a one-group C-X disconnection) with the acylation of carbon nucleophiles and move on to compare the 1,2-diX disconnection 3 with the alkylation of enolates 6. Here we have reversed the polarity. We mention regioselectivity—a theme we shall develop in chapter 14. 

The corresponding disconnection is of the newly formed C-C bond 8a. The synthons are the acyl cation and a nucleophilic carbon species that might be a metal derivative RM (chapter 13) but will generally be an enolate in the next 10 chapters. And that is how carbonyl compounds are nucleophilic. 

The disconnection is of the newly formed C-C bond 14a and is not the same as 8a. The synthons are represented by the enolate anion and a carbon electrophile. We saw alkyl halides in this role in chapter 13 but in the next 10 chapters we shall be mostly interested in combining enol(ate)s with carbonyl compounds. 

If we wish to make the diketone 24, disconnection to the same enolate 20 reveals the a3 synthon 25 and we already know that enone 26 is the reagent. Both these syntheses use synthons of natural polarity the enolate anion of one compound 22 and either a simple carbonyl compound 23 or the conjugated enone 26. 

This chapter deals with target molecules of two main types hydroxyketones 1 and 1,3- or P-diketones 4. Both have a 1,3-relationship between the two functionalised carbons. Both can be disconnected at one of the C-C bonds between the functional groups to reveal the enolate 2 of one carbonyl compound reacting with either an aldehyde 3 or acid derivative 5 such as an ester. 

The first disconnection for any a, 3-unsaturated carbonyl compound 21 is an FGI reversing the dehydration. We could suggest two alcohols 22 or 25 but we much prefer the 1,3-diO relationship in 22 to the 1,2-diO in 25 as the synthesis of compounds with odd numbered relationships needs synthons of only natural polarity (chapter 18). 

The last chapter introduced some good disconnections based on carbonyl compounds as both nucleophiles and electrophiles but avoided all questions of chemo- or regioselectivity. These reactions are so important that you need to understand how to control these issues. All the chief difficulties crop up in the synthesis of the conjugated enone 1. 

Fortunately, we know from the last chapter how to make a,j3-unsaturated carbonyl compounds so the disconnection of the enone 3 poses no problems. Both starting materials are ketones one 4 must provide the specific enolate and the other 16 the enone 3 by the Mannich reaction. 

We used this strategy in chapter 6 under two-group C-X disconnections where bromination of ketones was the usual functionalisation. More relevant here are conversions of carbonyl compounds into 1,2-dicarbonyl compounds by reaction with selenium dioxide SeC>2 or by nitrosation. So acetophenone 57 gives the ketoaldehyde10 58 with SeC>2. These 1,2-dicarbonyl compounds are unstable but the crystalline hydrate 59 is stable and 58 can be reformed on heating. Since aromatic ketones such as 57 would certainly be made by a Friedel-Crafts reaction the disconnection 58a is not between the two carbonyl groups and offers an alternative strategy. 

The bicyclic ketone 13 was made from the simpler enone 14 that also had to be made. Aldol (a, -unsaturated carbonyl compound—still our first choice) disconnection reveals the keto-aldehyde 15. 

Thus both unsaturated carbonyl compounds 27 and 30 disconnect to the same 1,6-dicarbonyl compound 28 that reconnects to natural limonene 29. There are two chemo-selectivity problems... 

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