Enol carbonates, formation

Both parts of the Lapworth mechanism enol formation and enol halogenation are new to us Let s examine them m reverse order We can understand enol halogenation by analogy to halogen addition to alkenes An enol is a very reactive kind of alkene Its carbon-carbon double bond bears an electron releasing hydroxyl group which makes it electron rich and activates it toward attack by electrophiles... 

Our experience to this point has been that C—H bonds are not very acidic Com pared with most hydrocarbons however aldehydes and ketones have relatively acidic protons on their a carbon atoms pA s for enolate formation from simple aldehydes and ketones are m the 16 to 20 range... 

An important feature of aldol addition is that carbon-carbon bond formation occurs between the a carbon atom of one aldehyde and the carbonyl group of another This is because carbanion (enolate) generation can involve proton abstraction only from the a carbon atom The overall transformation can be represented schematically as shown m Figure 18 5... 

You have already had considerable experience with carbanionic compounds and their applications in synthetic organic chemistry The first was acetyhde ion m Chapter 9 followed m Chapter 14 by organometallic compounds—Grignard reagents for example—that act as sources of negatively polarized carbon In Chapter 18 you learned that enolate ions—reactive intermediates generated from aldehydes and ketones—are nucleophilic and that this property can be used to advantage as a method for carbon-carbon bond formation... 

Site-specificity of the reaction is established in the first step since enolate formation involves the carbonyl carbon and the former halide bearing carbon, while the stereospecificity of the incoming deuterium is determined during the second step. It appears that the ketonization in deuterioacetic acid yields mainly the kinetic product (axial attack) although deuteration is... 

A reaction of great synthetic value for carbon-carbon bond formation. Nucleophilic addition of an enolate ion to a carbonyl group, followed by dehydration of the p-hydroxy aldehyde, yields an a,p-unsaturated aldehyde. 

The overall process is the addition of a CH-acidic compound to the carbon-carbon double bond of an o ,/3-unsaturated carbonyl compound. The Michael reaction is of particular importance in organic synthesis for the construction of the carbon skeleton. The above CH-acidic compounds usually do not add to ordinary carbon-carbon double bonds. Another and even more versatile method for carbon-carbon bond formation that employs enolates as reactive species is the aldol reaction. 

Figure 22.1 MECHANISM Mechanism of acid-catalyzed enol formation. The protonated intermediate can lose H+, either from the oxygen atom to regenerate the kelo tautomer or from the a carbon atom to yield an enol.

Mechanism of base-catalyzed enol formation. The intermediate enolate ion, a resonance hybrid of two forms, can be protonated either on carbon to regenerate the starting keto tautomer or on oxygen to give an enol. 

Vinyl sulfones, being good Michael acceptors, have been regarded as useful reagents for carbon-carbon bond formation. Nucleophiles used often are organometallic reagents, enamines and enolate anions and the Michael addition products are usually obtained in... 

For general reviews of enolate alkylation, see D. Caine, in Carbon-Carbon Bond Formation, Vol. 1, R. L. Augustine, ed., Marcel Dekker, New York, 1979, Chap. 2 C. H. Heathcock, Modem Synthetic Methods, 6, 1 (1992). 

Chapters 1 and 2 focus on enolates and other carbon nucleophiles in synthesis. Chapter 1 discusses enolate formation and alkylation. Chapter 2 broadens the discussion to other carbon nucleophiles in the context of the generalized aldol reaction, which includes the Wittig, Peterson, and Julia olefination reactions. The chapter and considers the stereochemistry of the aldol reaction in some detail, including the use of chiral auxiliaries and enantioselective catalysts. 

Enzyme Catalyzed. The enzyme aldolases are the most important catalysts for catalyzing carbon-carbon bond formations in nature.248 A multienzyme system has also been developed for forming C-C bonds.249 Recently, an antibody was developed by Schultz and co-workers that can catalyze the retro-aldol reaction and Henry-type reactions.250 These results demonstrate that antibodies can stabilize the aldol transition state but point to the need for improved strategies for enolate formation under aqueous conditions. 

The carbonyl group in a ketone or aldehyde is an extremely versatile vehicle for the introduction of functionality. Reaction can occur at the carbonyl carbon atom using the carbonyl group as an electrophile or through enolate formation upon removal of an acidic proton at the adjacent carbon atom. Although the carbonyl group is an integral part of the nucleophile, a carbonyl compound can also be considered as an enophile when involved in an asymmetric carbonyl-ene reaction or dienophile in an asymmetric hetero Diels-Alder reaction. These two types of reaction are discussed in the next three chapters. 

Besides the allylation reactions, imines can also undergo enol silyl ether addition as with carbonyl compounds. Carbon-carbon bond formation involving the addition of resonance-stabilized nucleophiles such as enols and enolates or enol ethers to iminium salt or imine can be referred to as a Mannich reaction, and this is one of the most important classes of reactions in organic synthesis.104... 

Polyenes are most often synthesized by cross-coupling reactions between unsaturated systems. Typically these reactions require an activated carbon, often in the form of an organometallic reagent. Enolates and phosphonium ylides, Wittig-type reagents, are also commonly employed in carbon-carbon bond formation. Pericyclic rearrangements also result in the generation of new carbon-carbon bonds and will be treated separately. 

Oxidation of silyl enol ethers leading to carbon-carbon bond formation [85JCS(CC)420 87JCS(P1)559] finds an interesting application in the synthesis of furans. For example, l,4-di(3-thienyl)-l,4-butanedione (65), which... 

The [1,4]-Wittig rearrangement is potentially useful not only for the carbon-carbon bond formation but also for enolate formation. However, synthetic applications have been rather limited, because of the low yields and restricted range of substrates. Schlosser s group have developed a practical approach to aldehydes based on a [1,4]-rearrangement/ enolate trapping sequence. In contrast, standard aqueous workup gave poor yield of aldehyde. This protocol was employed as the key step in a synthesis of pheromone (102) from 99 via 100 and 101 (equation 56f. ... 

By means of in situ NMR spectroscopy combined with deuterium incorporation experiments, van Leeuwen has elucidated the mechanism of termination by protonolysis, showing that the fl-chelates are in equilibrium with their enolate form by a p-H elimination/hydride migration process (Scheme 7.19). The enolate intermediates are regioselectively protonated at the C2 carbon atom by either MeOH or H2O to give Pd-OMe or Pd-OH and keto terminated copolymer. The enolate formation has been reported to be rate determining in the chain transfer [19]. 

One problem in the anti-selective Michael additions of A-metalated azomethine ylides is ready epimerization after the stereoselective carbon-carbon bond formation. The use of the camphor imines of ot-amino esters should work effectively because camphor is a readily available bulky chiral ketone. With the camphor auxiliary, high asymmetric induction as well as complete inhibition of the undesired epimerization is expected. The lithium enolates derived from the camphor imines of ot-amino esters have been used by McIntosh s group for asymmetric alkylations (106-109). Their Michael additions to some a, p-unsaturated carbonyl compounds have now been examined, but no diastereoselectivity has been observed (108). It is also known that the A-pinanylidene-substituted a-amino esters function as excellent Michael donors in asymmetric Michael additions (110). Lithiation of the camphor... 

In a similar manner to that described for bicyclic lactams (Section 1.1.1.3.3.4.1.5.I.). alkylation reactions of tricyclic lactams, which contain a fused benzene ring adjacent to the carbon undergoing alkylation, have been exploited14. The first alkylation of the benzo-annulated bicyclic lactam 1 gives a mixture of diastereomers, which is then further alkylated. In the second alkylation step, the counterion on the alkoxide, which is formed prior to enolate formation, proved to be crucial for the diastereoselectivity of the subsequent alkylation reaction. The best diastcrcoselectivity was obtained when either dichlorobis(ij5-cyclopentadienyl)zirconium or triisopropoxytitanium chloride was added to the preformed alkoxide, followed by enolization and alkylation. Using this method the second alkylation step gives a satisfactory diastereoselectivity. Hydride reduction of the purified major diastereomer 2, followed by acid treatment of the product, furnishes chiral naphthalenones 414. 

Inter- and intramolecular reactions between a propargyiic carbocation equivalent stabilized by Co2(CO)6-coordination and enol derivatives also provide a good method for the carbon-carbon bond formation at the propargyiic carbon of propargyiic alcohols and their derivatives. Many diastereoselective and enantioselective propargyiic alkylation reactions at the propargyiic position take place between chiral propargyiic cation equivalents and enol derivatives. 

To determine whether the differences in stilbene photostationary state they observed with these sensitizers were due to sensitization or to quenching by the enol, its formation was studied by flash kinetic spectroscopy. The observation that both piperylene and stilbene strongly quenched enol formation suggests that enolization of a ketone in which an abstractable hydrogen is bonded to carbon is much more easily quenched than enolization of one in... 

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