Enol ethers, protonation

The benzene rings A and B derived from the H NMR spectrum can be completed using Table 41.1. The way in which the enol ether is bonded is indicated by the correlation signal of the proton at Sh = 8.48. The structural fragment C results. Incorporating the C atom resonating at 5c = 123.3, which has not been accommodated in ring A or B and which is two bonds Jch) removed from the enol ether proton. 

Enol ether protons are interesting in that their chemical shifts are unusually high field in comparison with other alkenes on account of lone pair donation into the double bond from oxygen (Structure 5.5). No special precautions are necessary when dealing with them as this is reflected in the values obtained using Table 5.6. 

Triphenylpyrylium undergoes exchange at the 3- and 5-positions in hot deuterioacetic acid, but the process probably involves, not protonation of the pyrylium cation, but formation of an equilibrium concentration of an adduct, with acetate added to C-2, allowing enol ether protonation and thus exchange. ... 

Silicon Enolates Silyl enol ethers are well known as stable and easily handled enolates. Several research groups took advantage of this higher stability to develop new and innovative enantioselective protonation protocols (Scheme 31.16). ° However, despite the impressive advances made in the development of enantioselective silyl enol ether protonation the last 20 years, then-use as a synthetically useful tool remains sporadic. Indeed, to the best of our knowledge, there has only been a sole report that was applied to the enantioselective silyl enol ether protonation as a key step for natural product synthesis.i° ° i""... 

The ketone is added to a large excess of a strong base at low temperature, usually LDA in THF at -78 °C. The more acidic and less sterically hindered proton is removed in a kineti-cally controlled reaction. The equilibrium with a thermodynamically more stable enolate (generally the one which is more stabilized by substituents) is only reached very slowly (H.O. House, 1977), and the kinetic enolates may be trapped and isolated as silyl enol ethers (J.K. Rasmussen, 1977 H.O. House, 1969). If, on the other hand, a weak acid is added to the solution, e.g. an excess of the non-ionized ketone or a non-nucleophilic alcohol such as cert-butanol, then the tautomeric enolate is preferentially formed (stabilized mostly by hyperconjugation effects). The rate of approach to equilibrium is particularly slow with lithium as the counterion and much faster with potassium or sodium. 

Selective reduction of a benzene ring (W. Grimme, 1970) or a C C double bond (J.E. Cole, 1962) in the presence of protected carbonyl groups (acetals or enol ethers) has been achieved by Birch reduction. Selective reduction of the C—C double bond of an a,ft-unsaturated ketone in the presence of a benzene ring is also possible in aprotic solution, because the benzene ring is redueed only very slowly in the absence of a proton donor (D. Caine, 1976). 

The keto-carbonyl C signal at 5c = 200.9 would only fit the aflatoxins B, and M,. In the C NMR spectrum an enol ether-C// fragment can also be recognised from the chemical shift value of 5c = 145.8 and the typical one-bond coupling constant Jch = 196 Hz the proton involved appears at Sh = 72, as the CH COSY plot shows. The H triplet which belongs to it overlaps with a sing-... 

Direct treatment of TIPS enol ethers of a variety of cyclic and acyclic ketones with the strong-base combination of n-BuLi/KO-t-Bu leads to /3-ketosilanes (2) after aqueous work-up. In contrast with the earlier method, this rearrangement appears to proceed through allylic, rather than vinylic, metallation, since enol ethers lacking an allylic a-proton are unreactive. 

Figure 3.3 Antibody 14D9 catalyzes the enantioselective protonation of enol ethers.

The molecular mechanism of the enantioselective protonation reaction by antibody 14D9 was revealed by a crystal structure analysis [19[. A catalytic carboxyl group AspH 101 was found at the bottom of the catalytic pocket and found to be necessary for catalysis by mutagenesis to Asn or Ala. The mechanism or protonation involves an overall syn addition of water to the enol ether in a chiral binding pocket ensuring complete enantioselectivity (Figure 3.4). 

Enol ethers are readily hydrolyzed by acids the rate-determining step is protonation of the substrate. However, protonation does not take place at the oxygen but at the p carbon, because that gives rise to the stable carbocation 104. After that, the mechanism is similar to the A1 mechanism given above for the hydrolysis of acetals. 

The acid-catalyzed hydrolysis of enol esters (RCOOCR =CR) can take place either by the normal Aac2 mechanism or by a mechanism involving initial protonation on the double-bond carbon, similar to the mechanism for the hydrolysis of enol ethers given in 10-6, ° depending on reaction conditions. In either case, the products are the carboxylic acid RCOOH and the aldehyde or ketone R2" CHCOR. ... 

The structure of the products is determined by the site of protonation of the radical anion intermediate formed after the first electron transfer step. In general, ERG substituents favor protonation at the ortho position, whereas EWGs favor protonation at the para position.215 Addition of a second electron gives a pentadienyl anion, which is protonated at the center carbon. As a result, 2,5-dihydro products are formed with alkyl or alkoxy substituents and 1,4-products are formed from EWG substituents. The preference for protonation of the central carbon of the pentadienyl anion is believed to be the result of the greater 1,2 and 4,5 bond order and a higher concentration of negative charge at C(3).216 The reduction of methoxybenzenes is of importance in the synthesis of cyclohexenones via hydrolysis of the intermediate enol ethers. 

In this section, we will look at alkene, imine, enol ether and alkyne protons. It s convenient to consider the first three at this stage as they usually absorb in the 8-5 delta region and the alkyne is included here for convenience. 

Enantioselective protonation of silyl enol ethers using a SnCl4-BINOL system has been developed (Scheme 83). 45 This Lewis-acid-assisted chiral Bronsted acid (LBA) is a highly effective chiral proton donor. In further studies, combined use of a catalytic amount of SnCl4, a BINOL derivative, and a stoichiometric amount of an achiral proton source is found to be effective for the reaction.346 347... 

Enol ether additives were used to probe the protonation of 3-cyclopen-tenylidene (127). Treatment of A-nitroso-A-(2-vinylcyclopropyl)urea (124) with sodium methoxide generates 2-vinylcyclopropylidene (126) by way of the labile diazo compound 125 (Scheme 25). For simplicity, products derived directly from 126 (allene, ether, cycloadduct) are not shown in Scheme 25. The Skat-tebpl rearrangement of 126 generates 127 whose protonation leads to the 3-cyclopentenyl cation (128). In the presence of methanol, cyclopentadiene (130) and 3-methoxycyclopentene (132) were obtained.53 With an equimolar mixture of methyl vinyl ether and methanol, cycloaddition of 127 (—> 131)... 

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