Conjugate addition carboxylic acid derivatives

The asymmetric synthesis of / -branched carboxylic acid derivatives was accomplished by conjugate addition of mixed organoaluminum reagents to optically active Arabinose-derived c -unsaturated A-acyloxazolidinones (Scheme 47). Efficient stereocontrol was achieved using different optically active bicyclic oxazolidinones, yielding (.R)- or ( -configured / -branched carboxylic acid derivatives.136a... 

Reduction of a., -unsaturated carbonyl compounds. Hydrosilanes, particularly (QH,)2SiH2, in the presence of Pd(0), and a Lewis acid, particularly ZnCl2, can effect selective conjugate reduction of unsaturated ketones, aldehydes, and carboxylic acid derivatives. Chloroform is the solvent of choice. In addition, 1 equiv. of water is required. Experiments with D,0 and (C6H,),SiD2 indicate that... 

The same type of reaction has been applied to the preparation of 1,2-dihydroquinoline-3- and 277-l-benzothiopyran-3-carboxylic acid derivatives (equation 38) via a magnesium amide-induced sequential conjugate addition-aldol condensation reaction between 2-(alkylamino)phenylketones or 2-mercaptobenzophenones . 

This chapter will be divided into sections according to the electrophiles aldehydes and ketones, imines and iminium salts, carboxylic acid derivatives and finally a,P-unsaturated carbonyl compounds, which undergo conjugate additions. Further subdivision will be made according to the nature of the nucleophile, i.e. 0-, N-, S-, P- or C-nucleophiles. Finally, multicomponent heterocyclic syntheses will be mentioned, if they consist at least of one iron-catalyzed addition step to a carbonyl compound. 

Rueck, K, Kunz, H, Stereoselective conjugate addition of organoaluminum chlorides to a,(i-unsaturated carboxylic acid derivatives. Synthesis, 1018-1028, 1993. 

The Michael-type addition, a nucleophilic addition of an anion to the carbon-carbon double bond of an a,(3-unsaturated ketone, aldehyde, nitrile, nitro, sulphonyl, or carboxylic acid derivative, provides a powerful tool for carbon-carbon bond formation. The reaction is most successful with relatively nonbasic ( soft ) nucleophiles such as thiols, cyanide, primary and secondary amines, and P-dicarbonyl compounds. There is often a competition between direct attack on the carbonyl carbon (1,2-addition) and conjugate addition (1,4-addition) when the substrate is an a,(3-unsaturated carbonyl compound. 

Nucleophiles react with a, 8-unsaturated carboxylic acid derivatives with reactive carbonyl groups, such as acyl chlorides, to form nucleophilic acyl substitution products. Conjugate addition products are formed from the reaction of nucleophiles with less reactive carbonyl groups, such as ester and amides. 

In Section 18.13, you saw that nucleophiles react with o , 8-unsaturated aldehydes and ketones, forming either direct addition products or conjugate addition products in Section 18.14, you saw that nucleophiles react with o , S-unsaturated carboxylic acid derivatives, forming either nucleophilic acyl substitution products or conjugate addition products. 

So far we have shown you conjugate additions mainly of a,P-unsaturated aldehydes and unsaturated a,P-ketones. You won t be at all surprised to learn, however, that unsaturated acids, esters, amides, and nitriles—in fact all carboxylic acid derivatives—can also take part in conjugate addition reactions. Two examples, an amide and an ester, are shown on the right below. But notice how the selectivity of these reactions depends on the structure of the unsaturated compound compare the way butyllithium adds to this a,P-unsaturated aldehyde and a,P-unsaturated amide. Both additions are irreversible, and BuLi attacks the reactive carbonyl group of the aldehyde, but prefers conjugate addition to the less reactive amide. Similarly, ammonia reacts with this acyl chloride to give an amide product that derives from direct... 

The best alternatives to enamines for conjugate addition of enols of aldehyde, ketone, and carboxylic acid derivatives are silyl enol ethers. These stable neutral nucleophiles react very well with Michael acceptors either spontaneously or with Lewis acid catalysts such as TiCl4 at low temperature. If the 1,5-dicarbonyl compound is required, then an aqueous work-up with either acid or base cleaves the silicon—oxygen bond in the product. 

Conjugate Addition of Nitroalkanes to ot,P-Unsaturated Carboxylic Acid Derivatives... 

Diethylaluminium cyanide is a valuable reagent for the conjugate addition of HCN to o , 3-unsaturated carboxylic acid derivatives [120]. Steroidal conjugate esters are somewhat resistant to HCN addition even with this powerful reagent and optimum yields of only 36-50% were obtained. With aj3-unsaturated acid chlorides and acid cyanides, however, the reaction proceeds smoothly in toluene at room temperature and, after hydrolysis the 0-cyanoacid was obtained in 71—73% yield. Conjugated steroidal thiocarboxylic S-esters react under similar conditions to give the product in yields of 85-87%. 

As was the case with other similar carboxylic acid derivatives already discussed, nitriles do not absorb in the UV unless they have a,P-unsaturation. With only one a,P-double bond, most nitriles absorb with a in the range 210-220nm (Cmax == 10,000) additional conjugation moves the absorption maximum to longer wavelength. 

You learned in Chapter 17 that nucleophilic addition to aldehydes and ketones is one of the fundamental reaction types of organic chemistry, then in Chapter 19 you saw that addition to carbonyl groups in carboxylic acid derivatives can lead to nucleophilic acyl substitution. In this chapter, you ll encounter a third pattern of carbonyl reactivity—one that involves the enol tautomers of aldehydes, ketones, and esters and the conjugate bases of enols known as enolates. 

The conjugate addition of cyanide to a,p-unsaturated carboxylic acid derivatives provides versatile chiral building blocks. The resulting -cyano adducts can be converted into y-aminobutyric acids (GABA analogues) under reducing conditions, 1,2-dicarboxylic acids via hydrolysis, and -amino acids via Curtius rearrangement. 

An overview of organocatalysis based on NHC yet avoiding the formation of a Breslow intermediate (acyl anion equivalent) has appeared. It encompasses the conjugate addition of carbenes, their addition to carboxylic acid derivatives as well as ketenes and analogues and illustrates the wide chemical diversity that can be achieved through these processes. 

Reaction of an a, -unsaturated carboxylic acid derivative with a nucleophile forms a nucleophilic addition-elimination product with a reactive carbonyl group and a conjugate addition product with a less reactive carbonyl group (Section 17.19). 

R Cl R Br acyl phosphate a carboxylic acid derivative with a phosphate leaving group. 1,2-addition (direct addition) addition to the 1- and 2-positions of a conjugated system. 

Other electrophiles, such as Michael acceptors, can also be involved in the a-alkylation step. This has been exploited in the conjugate addition of enantiopure lithium amides 60 to unsaturated esters 61, followed by trapping of the resulting enolate with alkylidene malonates. This constitutes a useful methodology for the asymmetric synthesis of p-amino-a-substituted carboxylic acid derivatives 62 (Scheme 11.24) [65]. 

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