Reactions of enol ethers

Enols have an OH group and are alcohols of a sort. Normal alcohols form stable ethers that are difficult to convert back to the alcohol. Powerful reagents such as HI or BBr3 are required and these reactions were discussed in Chapter 17. The reaction with HI is an Sn2 attack on the methyl group of the protonated ether and that is why a good nucleophile for saturated carbon, such as iodide or bromide, is needed for the reaction. 

Enol ethers, by contrast, are relatively unstable compounds that are hydrolysed back to the carbonyl compound simply with aqueous acid. 

Hydrolysis of enol ether with aqueous acid 

Why the big difference The reason is that the enol ether can be protonated at carbon using the delocalization of the oxygen lone pair in the enol derivative to produce a reactive oxonium ion. 

This oxonium ion could be attacked on the methyl group in the same way that the ordinary ether was attacked. 

We wouldn t really expect this reaction to happen much faster than the same reaction on an ordinary ether, so there must be another better and faster mechanism. That mechanism is attack on the tc bond instead of attack on the a bond. 

In aqueous acid the nucleophile is just water and we find ourselves in the middle of the mechanism of hydrolysis of acetals (Chapter 11, p. 226). The oxonium ion is an intermediate common to both mechanisms. 

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The acid-catalyzed reaction of enol ethers 2 (X = OR) and enamines 2 (X = NR2) to form y-lactol derivatives proceeds with great ease even on silica gel chromatography. Vinyl sulfides 2 (X = SR) or vinyl chlorides 2 (X = Cl) are difficult to hydrolyze. 

The stereochemistry of these reactions depends on the lifetime of the dipolar intermediate, which, in turn, is influenced by the polarity of the solvent. In the reactions of enol ethers with tetracyanoethylene, the stereochemistry of the enol ether is retained in nonpolar solvents. In polar solvents, cycloaddition is nonstereospecific, as a result of a longer lifetime for the zwitterionic intermediate.177... 

In a similar manner, reaction of enol ether 2-787, hydroxycoumarin (2-781), and a-diketone 2-786 led to the cycloadduct 2-788 in 79% yield using Yb(OTf)3 as catalyst (Scheme 2.174). 2-788 could be transformed into the natural product preethulia coumarin (2-789). 

This result, associated with those on substituent effects, supports previous conclusions to the effect that the position of the transition state depends on the reactivity in agreement with RSP. In particular, stabilization of the intermediate as a result of conjugation, such as that in the reaction of enol ethers, makes the transition state very early. The few available KSIEs also suggest that the transition states for aromatic series are earlier than those for alkenes. 

T.-H. Chan, Formation and Addition Reactions of Enol Ethers In Comprehensive Organic Synthesis (Ed. B. M. Trost), Pergamon Press, New York, 1991, vol. 2, pp. 595-628. 

Alkoxy ketones. These ketones can be prepared by an aldol-type reaction of enol ethers with acetals catalyzed by a trityl salt. Methoxymethyl (MOM) enol ethers are more reactive than methyl enol ethers. 

The reaction of enol ethers with allenesulfonamides produces tetrahydropyridines with a novel 1,3-sulfonyl shift <99AG(E)121>. 

J. C. Lopez and B. Fraser-Reid, Serial radical reactions of enol ethers Ready routes to highly functionalized C-glycosyl derivatives, J. Am. Chem. Soc. 111 5450 (1989). 

Reaction of enol ether 1 a with sodium methoxidc or ethoxide. or 1 b with sodium methoxide, gives ketene acetals, which rearrange in the presence of triethylamine to give esters 3.3 The phosphorus ylide trimethoxy[2,2,2-trilluoro-l-(trifluoromethyl)cthylidene]-A ,-phosphane f(CF3)2C = P(OMc),] rearranges readily to dimethyl f2.2,2-trifluoro-1-mcthyl-l-(trifluoro-mcthyi)ethyl]phosphonate [(CF,)2C(Me)PO(OMe)2] in a similar 1.3-shift.5-0... 

The chiral bis(oxazoline)/Cu(II) complex with OTf or SbFg as a counter anion effectively promotes the enantioselective hetero Diels-Alder reaction of enol ethers with acyl phosphonates to give chiral enol phosphonates as synthetically useful chiral building blocks [64] (Eq. 8A.40). 

Ab initio molecular orbital calculations, coupled with activation energies and entropies from experimental data, have been employed to determine the nature of the intermediates in the reaction of singlet oxygen with alkenes, enol ethers, and enamines.214 Allylic alkenes probably react via a perepoxide-like conformation, whereas the more likely pathway for enamines involves a zwitterionic cycloaddition mechanism. The reactions of enol ethers are more complex, since the relative stabilities of the possible intermediates (biradical, perepoxide, and zwitterionic) here depend sensitively on the substituents and solvent polarity. 

Asymmetric aldol reactions.4 The borane complex 3 can also serve as the Lewis acid catalyst for the aldol reaction of enol silyl ethers with aldehydes (Mukaiyama reactions).5 Asymmetric induction is modest (80-85% ee) in reactions of enol ethers of methyl ketones, but can be as high as 96% ee in reactions of enol ethers of ethyl ketones. Moreover, the reaction is syn-selective, regardless of the geometry of the enol. However, the asymmetric induction is solvent-dependent, being higher in nitroethane than in dichloromethane. 

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... 

TABLE 10.3. Asymmetric Mannich Reactions of Enol Ethers with Alkynyl Imines... 

Novel complex heterocycles such as 2-148 can easily be obtained using the hetero Diels-Alder reaction of enol ethers like 2-147 and 2-146 as l-oxa-1,3-butadiene (Fig. 2-40) [149]. 

Reactions of enol ethers with halogen and sulfur electrophiles... 

C. Cycloaddition Reactions of Enol Ethers and of Dienes to the C=C Bond... 

The proximity of the diffusion limit also inhibits a detailed discussion of the data in Table 7, but a significant difference to the substituent effects discussed in Section III.D.4 is obvious. Whereas the reactivities of terminal alkenes, dienes, and styrenes toward AnPhCH correlate with the stabilities of the new carbenium ions and not with the ionization potentials of the 7r-nucleophiles [69], the situation is different for the reactions of enol ethers with (p-ClC6H4)2CH+ [136]. In this reaction series, methyl groups at the position of electrophilic attack activate the enol ether double bonds more than methyl groups at the new carbocationic center, i.e., the relative activation free enthalpies are not controlled any longer by the stabilities of the intermediate carbocations but by the ionization potentials of the enol ethers (Fig. 20). An interpretation of the correlation in Fig. 20 has not yet been given, but one can alternatively discuss early transition states which are controlled by frontier orbital interactions or the involvement of outer sphere electron transfer processes [220]. 

Table 1 Reaction of Enol Ethers and Acetates with Halogens...

The reaction of enol ether radical cations with hydroxide is six orders of magnitude faster than with water [249], but products have not been identified. In contrast, reaction of 37 and 38 with acetonitrile or methanol is very slow. In a comparative study, it was demonstrated that enol ether reacted much slower than enol ester radical cations with fluoride [227] affording ot-fluoroke-tones only in poor yield. Hitherto, reports in the literature give no evidence for the loss of an alkyl group from enol ether radical cations which would allow to enter ot-carbonyl radical and ot-carbonyl cation chemistry. 

An intramolecnlar palladium-mediated allylic alkylation via a ketone enolate of piperidinone 54 was reported by Williams and coworkers for the synthesis of R)-l-hydroxyquinine 57 (eqnations 17 and 18) °. The key step involves a palladium-mediated Sjv2 -type cyclization reaction of enol ether 55 in the presence of BnsSnF, giving rise to a quinuclidine ketone, which was immediately rednced to 56 to avoid equilibration and /3-elimination. Interestingly, none of the undesired C3-vinyl stereoisomer was observed. 

Table 5 Boron-ene Reactions of Enol Ethers Preparation of 1,4-Dienes (38)...

Another type of pre-formed reagent (28) has been used to carry out diastereose-lective Mannich reactions. The lithium salts 27 are treated with TiCU to give 28, which is then treated with the enolate of a ketone." ° The palladium catalyzed Mannich reaction of enol ethers to imines is also known." ° The reaction of silyl enol ethers and imines is catalyzed by HBF4 in aqueous methanol." ° Similarly, silyl enol ethers react with aldehydes and aniline in the presence of InCla to give the p-amino ketone." ° Imines react on Montmorillonite KIO clay and microwave irra-... 

Prepared in situ in the Simmons-Smith reaction of enol ethers. 

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