Enol ethers reactions with electrophilic carbon

Arynes react readily with simple alkenes to give either benzocyclobutenes or substituted benzenes (Scheme 7.31). The formation of benzocyclobutenes by [2+2] cycloaddition reaction of the aryne to the alkene proceeds best for strained and electron-rich carbon-carbon (C=C) double bonds. For example, dicyclopentadiene reacts to give the ex o-isomer of the corresponding four-membered ring in good yield. The addition to cyanoethene (acrylonitrile) and the reaction with the electron-rich ethoxyethene (ethyl vinyl ether) gives the cyano- and ethoxy-benzocyclobutenes in 20% and 40% yields, respectively. The latter reaction almost certainly involves nucleophilic addition of the enol ether to the electrophilic aryne followed by coUapse... 

The Mukaiyama-aldol reaction of silyl enol ethers is one of the most important carbon-carbon bond-forming reactions in organic synthesis. Therefore, its application to catalytic asymmetric synthesis has been investigated in depth for the last decade (52-56). In an analogy to the F-C reaction of vinyl ether, if a catalytic asymmetric F-C reaction proceeds under Mukaiyama conditions to give additional reactive silyl enol hers, sequential reactions with electrophiles could provide further functionalized products (chiral syn or a fi-a,/8-dihydroxythioesters as a-... 

As mentioned earlier, metal complexation not only allows isolation of the QM derivatives but can also dramatically modify their reactivity patterns.29o-QMs are important intermediates in numerous synthetic and biological processes, in which the exocyclic carbon exhibits an electrophilic character.30-33 In contrast, a metal-stabilized o-QM can react as a base or nucleophile (Scheme 3.16).29 For instance, protonation of the Ir-T 4-QM complex 24 by one equivalent of HBF4 gave the initial oxo-dienyl complex 25, while in the presence of an excess of acid the dicationic complex 26 was obtained. Reaction of 24 with I2 led to the formation of new oxo-dienyl complex 27, instead of the expected oxidation of the complex and elimination of the free o-QM. Such reactivity of the exocyclic methylene group can be compared with the reactivity of electron-rich enol acetates or enol silyl ethers, which undergo electrophilic iodination.34... 

The scope of the acid-catalyzed formation of C-glycosyl compounds has been greatly expanded with the finding that enol ethers and ketene acetals can be used as the carbon source in electrophilic substitution reactions at the anomeric center.126 Treatment of 198 with the trimethylsilyl enol ether derived from cyclohexanone, in the presence of stannic chloride, led to 2-(2,3,5-tri-0-benzoyl-/J-D-ribofuranosyl)cyelohexanone (206), presumably by way of the inter-... 

Having defined the types of commonly used carbon nucleophiles and carbon electrophiles, it would seem that if you react any of the carbon nucleophiles (electron donors) with any of the carbon electrophiles (electron acceptors), then a carbon-carbon bond should be formed. While this is theoretically true, it is unworkable from a practical point of view. If, for example, a carbanion nucleophile was reacted with a cationic electrophile, it is unlikely that the desired carbon-carbon bond formation would be detected, even after the smoke cleared. Or if a silyl enol ether nucleophile was reacted with an a, /f-unsaturated ester, no reaction could be observed to take place in any reasonable time frame. 

Silyl enol ethers are quite reactive towards IOB-boron trifluoride (or tetrafluoroboric acid) and can be considered as valuable starting materials for several reactions of synthetic importance. Of special interest is their use for carbon-carbon bond formation 1,4-diketones and unsaturated ketones are the products of such reactions further, they can be transformed to oc-hydroxy, methoxy or trifyloxy ketones. With tetrafluoroboric acid IOB forms a yellow solution containing the highly electrophilic Phi+ OH BF4 , stable up to 0°C. This species reacts readily with silyl ethers of several ketones, notably acetophenones, at —78°C, forming an unstable iodonium ion (ArCOCH2I+ Ph) which with another silyl ether affords 1,4-diketones. 

Enamines are among the most powerful neutral nucleophiles and react spontaneously with alkyl halides. Silyl enol ethers are less reactive and so require a more potent electrophile to initiate reaction. Carbocations will do, and they can be generated in situ by abstraction of a halide or other leaving group from a saturated carbon centre by a Lewis acid. 

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. 

When the acetal and the silyl enol ether are mixed with the same Lewis acid catalyst, Noyori found that an efficient aldol-style condensation takes place with the acetal providing the electrophile. The reaction is successful at low temperatures and only a catalytic amount of the Lewis acid is needed. Under these conditions, with no acid or base, few side-reactions occur. Notice that the final desilylation is carried out by the triflate anion to regenerate the Lewis acid Me3Si-OTf. Triflate would be a very poor nucleophile for saturated carbon but is reasonable for silicon because oxygen is the nucleophilic atom. 

Among common carbon-carbon bond formation reactions involving carbanionic species, the nucleophilic substitution of alkyl halides with active methylene compounds in the presence of a base, e. g., malonic and acetoacetic ester syntheses, is one of the most well documented important methods in organic synthesis. Ketone enolates and protected ones such as vinyl silyl ethers are also versatile nucleophiles for the reaction with various electrophiles including alkyl halides. On the other hand, for the reaction of aryl halides with such nucleophiles to proceed, photostimulation or addition of transition metal catalysts or promoters is usually required, unless the halides are activated by strong electron-withdrawing substituents [7]. Of the metal species, palladium has proved to be especially useful, while copper may also be used in some reactions [81. Thus, aryl halides can react with a variety of substrates having acidic C-H bonds under palladium catalysis. 

The reaction with carbon tetrahalides [213] probably involves free-radical attack e.g. by CBra) rather than electrophilic attack on the enol, but is still subject to selection of the reaction site leading to the more stable conjugated product (c/. p. 159). The reaction with methyl chloride (and a base) has been described only in a patent [214], and no mechanistic details are available. It is surprising that so unreactive an electrophile should attack the enol ether. There is no clear reason for chloromethylation favouring C(4), beyond the suggestion [21 ] that the reagent may first form a complex with the 3-acetoxy group. 

The aldolization reaction is certainly the most popular reaction for creating carbon-carbon bonds and much effort has been made to achieve the reactions in smooth conditions with a high degree of stereoselectivity. The reaction involves activated carbonyl compounds (enol, enolates, various enol ethers) which add on another carbonyl compound or various electrophiles in related reactions. As most of the activated compounds are compatible with water, it is not surprising that the aldolization in aqueous conditions became an efficient process in view of the negative activation volume of the reaction. The diastereo-selectivity depends greatly on the reaction conditions. Thus, in a intramolecular aqueous aldolization, the acid-induced reaction of a keto aldehyde provided a syn hydroxy ketone while the base-catalyzed reaction led to the anti isomer (Scheme 35) [179]. 

It is clear that the addition reactions of enol ethers to C—ir-bonds are useful transformations in organic synthesis. Selectivity can be exercised with a range of enol ethers, with the proper choice of catalysts, and with a range of carbon electrophiles. The question of stereoselectivity of these reactions will be discussed in the next chapter. In the future, we can expect more new developments in this area including a better understanding of the structural and mechanistic details of these reactions. ... 

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