Reactions of Enolates and Enolate Equivalents

Reactions of Enolates and Enolate Equivalents.— Highly crowded ketones are prepared by the Lewis acid-catalysed t-alkylation of trimethylsilyl enol ethers. Stereoselection is observed in alkylations with tertiary halides which are known to solvolyse stereoselectively owing to anchimeric assistance or other factors. The alkylation can be carried out in an intramolecular fashion, but compounds having silyl enol ether and tertiary halide functions are difficult to prepare. However, Lewis acid-mediated cyclization of trisubstituted olefinic active methylene compounds provides an alternative method for the intramolecular 

Hofmann, and G. Simchen, Liebigs Ann. Chem., 1981,1643. 

Amidomethylation can be carried out by the reaction of silyl enol ethers with trialkylhexahydrotriazines and acetyl chloride [equation (63)].  

Bis(dibenzylideneacetonato)palladium in conjunction with l,2-bis(diphenyl-phosphino)ethane is a superior catalyst for the alkylation of lithium enolates with allylic acetates. Bis(pentan-2,4-dionato)palladium will catalyse the alkylation of pentan-2,4-dione by allylic alcohols, but the reaction is of limited value in its present form since the catalyst has been shown to cause rearrangements and disproportionation of allylic alcohols.  

Syntheses of /3-vetivone and /S-vetispirene have been used to demonstrate an intramolecular decarboxylative alkylation route to spirocyclic ketones which does not involve the use of strong base [equation (64)].  

Reactions of Enolates and Enolate Equivalents.—The Lewis-acid-induced a-alkylation of carbonyl compounds via reaction between silyl enol ethers and S Nl-active alkylating agents has been reviewed.  

Enolates may be trapped in a site-specific manner as their enol carbonates. Such derivatives show lower nucleophilicity than their silyl counterparts, and allow, inter alia, transformations to be carried out on isolated double bonds, whilst retaining the ability to regenerate the enolate regiospecifically on reaction 

Reagents i, RMgBr,Cu2lj,Me2S ii, Me3SiCI iii, Mc2N=CH2 Cl iv, Mel v, K2CO3 vi, MeLi 

Reagents i, LiNPri ii, CIC CCl iii, PhSC=CCl iv, PhCsCCl v, Hi.Lindlar catalyst vi, Cu.AcOH 

For the reductive removal of the sulphone group from adducts derived from P-keto-esters, higher yields were obtained by protection of the keto-group prior to reduction. 

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Aldol addition and related reactions of enolates and enolate equivalents are the subject of the first part of Chapter 2. These reactions provide powerful methods for controlling the stereochemistry in reactions that form hydroxyl- and methyl-substituted structures, such as those found in many antibiotics. We will see how the choice of the nucleophile, the other reagents (such as Lewis acids), and adjustment of reaction conditions can be used to control stereochemistry. We discuss the role of open, cyclic, and chelated transition structures in determining stereochemistry, and will also see how chiral auxiliaries and chiral catalysts can control the enantiose-lectivity of these reactions. Intramolecular aldol reactions, including the Robinson annulation are discussed. Other reactions included in Chapter 2 include Mannich, carbon acylation, and olefination reactions. The reactivity of other carbon nucleophiles including phosphonium ylides, phosphonate carbanions, sulfone anions, sulfonium ylides, and sulfoxonium ylides are also considered. 

Reactions of Enolates and Enolate Equivalents.—Several papers have appeared on the use of enolates released from silyl enol ethers by Lewis acids. Fleming reports the regiospecific alkylation of either the thermodynamic or the kinetic silyl enol ethers with chloromethyl phenyl sulphide in the presence of titanium(iv) chloride. Oxidative or reductive removal of the sulphur gives a-methylene- or a-methyl-ketones respectively (Scheme 69). ... 

Reactions of Enolates and Enolate Equivalents.—Alkoxysulphuranes, prepared in situ from alcohols and bis-(2,2,2-trifluoroethoxy)diphenylsulphurane, are C-alkylating agents towards silyl enol ethers in the presence of potassium fluoride. This method of activation of alcohols towards nucleophilic displace-... 

The Darzens condensation reaction has been used with a wide variety of enolate equivalents that have been covered elsewhere. A recent application of this important reaction was appljed toward the asymmetric synthesis of aziridine phosphonates by Davis and coworkers.In this application, a THF solution of sulfinimine 34 (0.37 mmol, >98% ee) and iodophosphonate 35 (0.74 mmol) was treated with LiHMDS (0.74 mmol) at -78 °C to give aziridine 36 in 75% yield. Treatment of 36 with MeMgBr removed the sulfinyl group to provide aziridine 37 in 72% yield. 

Further studies by Bode and co-workers have shown that enolate formation from a-chloroaldehydes and subsequent reaction with 4-oxo-enoates or unsaturated a-ketoesters 232 generates dihydropyranones 233 in excellent diastereo- and enantio-selectivities, and with impressively low catalyst loadings [90], This work has been extended to the generation of enolate equivalents from bisulfite adducts of a-haloaldehydes 234 under aqueous conditions (Scheme 12.50) [91]. 

Scheme 2.25 shows some examples of additions of enolate equivalents. A range of Lewis acid catalysts has been used in addition to TiCl4 and SnCl4. Entry 1 shows uses of a lanthanide catalyst. Entry 2 employs LiC104 as the catalyst. The reaction in Entry 3 includes a chiral auxiliary that controls the stereoselectivity the chiral auxiliary is released by a cyclization using (V-methylhydroxylamine. Entries 4 and 5 use the triphenylmethyl cation as a catalyst and Entries 6 and 7 use trimethylsilyl triflate and an enantioselective catalyst, respectively. 

Although the reaction of ketones and other carbonyl compounds with electrophiles such as bromine leads to substitution rather than addition, the mechanism of the reaction is closely related to electrophilic additions to alkenes. An enol, enolate, or enolate equivalent derived from the carbonyl compound is the nucleophile, and the electrophilic attack by the halogen is analogous to that on alkenes. The reaction is completed by restoration of the carbonyl bond, rather than by addition of a nucleophile. The acid- and base-catalyzed halogenation of ketones, which is discussed briefly in Section 6.4 of Part A, provide the most-studied examples of the reaction from a mechanistic perspective. 

Silyloxy)alkenes were first reported by Mukaiyama as the requisite latent enolate equivalent to react with aldehydes in the presence of Lewis acid activators. This process is now referred to as the Mukaiyama aldol reaction (Scheme 3-12). In the presence of Lewis acid, anti-aldol condensation products can be obtained in most cases via the reaction of aldehydes and silyl ketene acetals generated from propionates under kinetic control. 

When the 1,3-dicarbonyl substrate reacts twice via its activated methylene due to the presence of heteroatoms blocking the enolization process on other positions, spiranic systems are formed in the presence of two equivalents of aldehyde and an equivalent of urea (Scheme 15) [85]. The reaction can be promoted either in acetic acid as solvent or neat under microwave irradiations or in the presence of H3PW12O40 as catalyst. Finally, this technique for generating spiroheterocyclic products has been transferred to solid-supported methodology by immobilizing the 1,3-dicarbonyl partner onto a resin [86]. 

In 2000, Tanino and his co-workers developed the novel [5- -2]-cycloaddition reaction of a propargyiic cation equivalent bearing allylic silane 17 with enol silane 18 to give the corresponding cycloheptyne complexes 19 in good yields with an excellent diastereoselectivity (Scheme 3). While ceric ammonium nitrate (CAN) is generally used to... 

Chloro-l,3-dithiane (797) has been employed as a formyl cation equivalent . The morpholine enamines of a variety of aldehydes and ketones were shown to react with this dithiane to produce the a-(l,3-dithan-2-yl) aldehydes and ketones (798) in good yield (Scheme 186) (77TL2077). In direct analogy with this work, the reaction of enol silyl ethers with 2-ethoxy-l,3-dithiolane in the presence of zinc chloride has been reported to afford half-protected 1,3-dicarbonyl compounds (81TL3243). 

We had to be careful in chapter 25 when we wanted to add bromoketones 4 to enolates 3 to make the 1,4-dicarbonyl compound 5. We could not use a lithium enolate because it would be too basic. No such difficulties exist in the reaction of enolates with allylic halides such as 2. Any enol(ate) equivalent will do as there are no acidic hydrogens and allylic halides are good electrophiles for the Sn2 reaction. 

Tetrasubstituted pyrroles could be obtained by skeletal rearrangement of 1,3-oxazolidines, a reaction that is substantially accelerated by microwave irradiation. Dielectric heating of a 1,3-oxazolidine 7, absorbed on silica gel (1 g silica gel/mmol) for 5 min in a household MW oven (900 W power) cleanly afforded the 1,2,3,4-tetrasubstituted pyrrole 8 in 78% yield, thus reducing the reaction time from hours to minutes (Scheme 5) [24], 1,3-Oxazolidines are accessible in one-pot, two-step, solvent-free domino processes (see also Sect. 2.6). The first domino process, a multi-component reaction (MCR) between 2 equivalents of alkyl propiolate and 1 equivalent of aldehyde furnished enol ethers 9 (Scheme 5). Subsequent microwave-accelerated solvent-free reactions of enol ethers 9 with primary amines on silica support afforded intermediate 1,3-oxazolidines, which in situ rearranged to the tetrasubstituted pyrroles (2nd domino process). Performed in a one-pot format, these... 

We have considered the reactions of enolates and their equivalents with alkyl halides. In the next chapter we move on to consider the reactions of the same types of enolate equivalents with a different class of electrophiles carbonyl compounds themselves. 

We have spent some considerable time and effort in understanding the aldol reaction simply because it is one of the most important reactions in organic chemistry. In the next chapter you will see how these ideas can be extended with almost no addition of principles to the acylation of enolates—the reaction of enols, enolates, and specific enol equivalents with acid chlorides and esters. We hope that you will see that the ideas introduced in this chapter find immediate application in the next. 

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. 

The Patemo-Buchl reaction of furan and various aldehydes was shown to be a highly stereoselective photochemical version of the aldol reaction by S.L. Schreiber and co-workers in which the furan serves as an enolate equivalent. This strategy was applied to the total synthesis of the antifungal metabolite (+)-avenaciolide. The photocycloaddition of nonanal with excess furan proceeded in nearly quantitative yield, and the two out of the three required stereocenters were created in a single step. The photocycloadduct was first hydrogenated then hydrolyzed under acidic conditions. 

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... 

Formation and Addition Reactions of Enol Ethers 2J.3 REACTIONS WITH C—X ir-BONDS AND EQUIVALENTS... 

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. 

Carbon-carbon bond formation is a reaction of fundamental importance to the cellular metabolism of all living systems and includes alkylation reactions involving one and five carbon fragments as well as carboxylation reactions. In addition, a very common method of generating carbon-carbon bonds in biology includes the reactions of enolates and their equivalents (such as enamines) with aldehydes, ketones, keto acids, and esters. Reactions in which the enolate derives from an acyl thioester are Claisen condensations, whereas the remainder are classified as aldol reactions. 

Enol triflates, unlike phosphates, react with trialkylmanganates R3MnLi derived from equivalent Li2MnCl4 and RLi in the absence of Pd(0) to give mainly the coupling product1243 (equation 102). Furthermore, the reaction of enol triflates with certain... 

In 2013, the Chi group disclosed a substrate-independent selective generation of enolates over homoenolate equivalents in NHC-catalyzed reactions of enals and chalcones. Acid co-catalysts play vital roles in control of the reaction pathways, as the acid might promote the enal p-protonation by increasing the proton concentration. Also, the competing enolate/homoeno-late pathways were found to be sensitive to the steric bulkiness of the enal and enone substrates (Scheme 7.74). 

Preparation and chemical reactivity of 2-chromanols 13ARK(1)101. Reactions of salicylaldehyde and enolates or their equivalents Versatile synthetic routes to chromane derivatives 12BJ02166. 

Catalytic asymmetric formal [4-1-2] cycloaddition reactions offer a versatile and elegant approach to the asymmetric synthesis of six-membered heterocycles. In 2006, Bode and coworkers demonstrated NHC-catalysed generation of enolate equivalents from enals for enantioselective Diels-Alder reactions. Reaction with a,p-unsaturated imine 100 provided the dihy-dropyridinones 101 in good yield and with remarkable enantioselectivities (Scheme 20.44). 

In contrast to the extensive use of nitroolefins in asymmetric Michael additions [10], the vinylogous analogues, nitrodienes and nitroenynes, are less frequently utilized in the conjugate addition of enolate equivalents, despite the significant synthetic utility of the resulting products which possess carbonyl, nitro, and olefin functionalities. Likewise, studies on the hetero-Michael reaction with these acceptors have been very limited, possibly because of apprehension of the site-selectivity issue [11]. 

The Pd-catalyzed Claisen rearrangement of allyl vinyl ethers to give a-allylated carbonyl compounds is a synthetic equivalent to those allylation reactions of enolates, enamines, and imines discussed in Sects. B and C.i as well as to the Tsuj-Trost reaction discussed in other sections. Although it is mostly discussed in Part IX as a rearrangement reaction. 

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