Silyl enol ethers with carbonyl compounds

The crossed aldol reaction of silyl enol ethers with carbonyl compounds (Mukaiyama-aldol) was studied by Lubineau and co-workers... 

The enol content of simple aldehydes and ketones is low under standard acid-catalyzed conditions. Silyl enol ethers, often available free of regioisomers, are an important source of enol equivalents for nucleophilic addition reactions. The reaction of silyl enol ethers with carbonyl compounds in the presence of BF3 Et20, SnCl4, TiCl4 or InCl3 proceeds through an open transition state instead of a closed transition state and leads, after hydrolytic workup, to aldol products. 

Mukaiyama, T., Banno, K., Narasaka, K. New cross-aldol reactions. Reactions of silyl enol ethers with carbonyl compounds activated by titanium tetrachloride. J. Am. Chem. Soc. 1974, 96, 7503-7509. 

The reaction of silyl-enol ethers with carbonyl compounds, also known as the Mukaiyama-z Ao reaction 236,237), represents one of the most useful methods for the (stereoselective) construction of carbon-carbon bonds 238-240). As an example of special interest, the y-butenolide moiety is present in over 13,000 natural products and the coupling of silyloxy furans and aldehydes using chiral Lewis acids is one of the most versatile strategies for butenolide syntheses 241-243). 

The crossed aldol reaction of silyl enol ethers with carbonyl compounds (Mukaiyama aldol) was first studied by Lubineau and coworkers in aqueous solvents. Without any acid catalyst, these reactions took several days to complete. A major development was the use of water-tolerant Lewis acids for such reactions, pioneered by Kobayashi and coworkers. ... 

The aldol or aldol-type reaction is well recognized as one of the most important carbon-carbon bond forming reactions in organic synthesis. As shown in Scheme 8.1, two stereogenic centers could be generated in this aldol reaction. The classical aldol condensation between an aldehyde and a ketone is often catalyzed by a base or an acid. Another approach is the acid-catalyzed cross-aldol reaction of silyl enol ethers with carbonyl compounds, the so-called Mukaiyama reaction. 

Unsaturated 1,5-dicarbonyl compounds. The phenylthioalkylation of silyl enol ethers of carbonyl compounds (9, 521-522) can be extended to the synthesis of unsaturated 1,5-dicarbonyl compounds. In a typical reaction the enol silyl ether of a ketone is alkylated with the unsaturated chloride 1 under ZnBr2 catalysis to give a homoallyl sulfide. Ozonolysis of the methylene group is accompanied by oxidation of the phenylthio group sulfoxide elimination results in an unsaturated 1,5-aldehydo ketone (equation I). Alkylation with 2 results in a methyl ketone (equation II). 

This procedure illustrates a general method for the preparation of crossed aldols. The aldol reaction between various silyl enol ethers and carbonyl compounds proceeds smoothly according to the same procedure (see Table I). Sllyl enol ethers react with aldehydes at -78°C, and with ketones near 0°C. Note that the aldol reaction of sllyl enol ethers with ketones affords good yields of crossed aldols which are generally difficult to prepare using lithium or boron enolates. Lewis acids such as tin tetrachloride and boron trifluoride etherate also promote the reaction however, titanium tetrachloride is generally the most effective catalyst. 

The other side of the coin is that the S 2 reaction at carbon is not much affected by partial positive [ charge (5+) on the carbon a tom. The Sn2 reaction at silicon is affected by the charge on silicon. The r most electrophilic silicon compounds are the silyl triflates and it is estimated that they react some 108-109 times faster with oxygen nucleophiles than do silyl chlorides. Trimethylsilyl triflate is, in fact, an excellent Lewis acid and can be used to form acetals or silyl enol ethers from carbonyl compounds, and to react these two together in aldol-style reactions. In all three reactions the triflate attacks an oxygen atom. 

This chapter is concerned with the reactions of enol ethers with carbonyl compounds as illustrated in Scheme 1. The enol ethers considered include alkyl, silyl, germyl and stannyl ethers, and to a small extent enol esters. The carbonyl compounds encompass aldehydes, ketones, esters and their functional equivalents. Overall, the reaction depicted in Scheme 1 is similar to the classical aldol and related condensations discussed in Part 1 of this volume. However, in contrast to the basic conditions inherent in... 

The catalyzed reaction of enol ethers with carbonyl compounds (Scheme 1) has become an important reaction in synthesis. Compared to the metal enolate reactions (Part 1, Volume 2), the catalyz enol ether reactions offer the following distinct differences. Enol ethers are often isolable, stable covalent compounds, whereas the metal enolates are usually generated and used in situ. Under Lewis acid catalyzed conditions, a number of functional equivalents such as acetals, orthoesters, thioacetals, a-halo ethers and sulfides can participate as the electrophilic components, whereas many of them are normally unreactive towards metal enolates. In synthesis, enol ether reactions now rival and complement the enolate reactions in usefulness. Enol silyl ethers are particularly useful because of their ease of preparation, their reasonable reactivity and the mildness of the desilylation process. 

Silyl enol ethers are powerful intermediates in organic synthesis. Reactions of silyl enol ethers with various electrophiles provide effective methods for the synthesis of various carbonyl compounds. In this section we will briefly touch on the electrochemical reactions of silyl enol ethers and related compounds. The electrochemical behaviour of silyl enol ethers is expected to be closely related to that of allylsilanes and benzylsilanes because silyl enol ethers also have a silyl group ft to the re-system. 

Perhaps the most useful type of alkene substrates for these reactions are enol ethers, enol esters and vinyl sulfides. Silyl enol ethers have excellent electron-donor properties, with an ionization potential of about 8 eV and an oxidation potential in various solvents of approximately 1.0-1.5 V vs SCE161. These compounds are easily synthesized by reaction of an enolate with a chlorosilane. (A very recent report synthesized a variety of silyl enol ethers with extremely high stereochemical yield, using the electrogenerated amidate of 2-pyrolidinone as the base.)162 An interesting point is that the use of oxidative or reductive cyclization reactions allows carbonyl functionalities to be ambivalent, either oxidizable or reducible (Scheme 65)163. 

The reaction of enol trimethylsilyl ethers of carbonyl compounds with (a,a-dihydroperfluoroalkyl) phenyliodonium triflates required promotion by potassium fluoride to proceed at room temperature to give the P-perfluoroalkyl carbonyl compounds in good yields.225 in the case of the silyl enol ether of an a,p-unsaturated ketone (119), the 6-perfluoroalkyl-o,p-unsaturated carbonyl compound (120) was the only product formed. The reaction is likely to follow a path similar to the one used in the reaction of silyl enol ethers with (perfluoroalkyl)phenyliodonium salts. In a first step, a ic-complex is formed which evolves into the cationic product of a- or y-addition, followed by desilylation to the carbonyl reaction product. 

Sulfenylation of lithium enolates with PhS-SPh or of silyl enol ethers with PhS-Cl allows any a-PhS carbonyl compound to be made regioselectively, e.g. 149 and 152 from 147 (see chapter 5). Oxidation with sodium periodate gives the sulfoxide without over-oxidation to the sulfone, but elimination requires reasonably high temperatures (about 120 °C for MeSO but only about 50 °C for PhSO). Together with the unpleasant by-products, the results of disproportionation of unstable PhSOH, this has led to a preference for the selenium version of the reaction, though we must admit that the by-products are even more offensive.22... 

In 1974, Mukaiyama and his coworkers reported on the Lewis acid promoted condensation of enol silyl ethers with carbonyl compounds to give the cross-aldol products." The reaction usually proceeds with retention of the regiochemical integrity of the starting enol silyl ethers as shown by those illustrated in Scheme 34. However, occasional examples of loss of regiointegrity of the starting enol silyl ethers have been noted in the literature. "... 

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