Enol ethers as nucleophiles

Ketone Enolates Derived from Silyl Enol Ethers as Nucleophiles... 

Scheme 9.15 Alkylations with ketone enolates derived from silyl enol ethers as nucleophiles.

Even if silicon chemistry is new to you, you should by now have a picture of stable compounds with C-Si bonds and selective reaction with fluoride. You are already familiar with silyl enol ethers as nucleophilic enolate equivalents and allyl silanes resemble these in many ways. The missing link is the i-silyl effect. A Si atom stabilises a cation in the p-posit ion by overlap of the populated and relatively high energy C-Si c-orbital with the empty p orbital of the cation. This overlap is already present in the preferred conformation 95a of the allyl silane 95 as an anti-bonding interaction 95b between the C-Si c-orbital and the n orbital of the double bond. The resultant molecular orbital (the new HOMO) 95c increases the nucleophilic reactivity of the carbon atom in the y-position. 

Alternatively, the iminium-activation strategy has also been apphed to the Mukaiyama-Michael reaction, which involves the use of silyl enol ethers as nucleophiles. In this context, imidazolidinone 50a was identified as an excellent chiral catalyst for the enantioselective conjugate addition of silyloxyfuran to a,p-unsaturated aldehydes, providing a direct and efficient route to the y-butenolide architecture (Scheme 3.15). This is a clear example of the chemical complementarity between organocatalysis and transition-metal catalysis, with the latter usually furnishing the 1,2-addition product (Mukaiyama aldol) while the former proceeds via 1,4-addition when ambident electrophiles such as a,p-unsaturated aldehydes are employed. This reaction needed the incorporation of 2,4-dinitrobenzoic acid (DNBA) as a Bronsted acid co-catalyst assisting the formation of the intermediate iminium ion, and also two equivalents of water had to be included as additive for the reaction to proceed to completion, which... 

The Mukaiyama aldol reaction is a highly selective cross aldol condensation using a silyl enol ether as nucleophile and a Lewis acid-coordinated carbonyl compound as electrophile. 

Reaction conditions that involve other enolate derivatives as nucleophiles have been developed, including boron enolates and enolates with titanium, tin, or zirconium as the metal. These systems are discussed in detail in the sections that follow, and in Section 2.1.2.5, we discuss reactions that involve covalent enolate equivalents, particularly silyl enol ethers. Scheme 2.1 illustrates some of the procedures that have been developed. A variety of carbon nucleophiles are represented in Scheme 2.1, including lithium and boron enolates, as well as titanium and tin derivatives, but in... 

Scheme 2.2 illustrates several examples of the Mukaiyama aldol reaction. Entries 1 to 3 are cases of addition reactions with silyl enol ethers as the nucleophile and TiCl4 as the Lewis acid. Entry 2 demonstrates steric approach control with respect to the silyl enol ether, but in this case the relative configuration of the hydroxyl group was not assigned. Entry 4 shows a fully substituted silyl enol ether. The favored product places the larger C(2) substituent syn to the hydroxy group. Entry 5 uses a silyl ketene thioacetal. This reaction proceeds through an open TS and favors the anti product. 

Radical cations of 2-alkylidene-l,3-dithianes can be generated electrochemically by anodic oxidation using a reticulated vitreous carbon (RVC) anode <2002TL7159>. These intermediates readily react with nucleophiles at C-1. Upon removal of the second electron, the sulfur-stabilized cations were trapped by nucleophilic solvents, such as MeOH, to furnish the final cycloaddition products. Hydroxy groups <20010L1729> and secondary amides <2005OL3553> were employed as O-nucleophiles and enol ethers as C-nucleophiles (Scheme 50) <2002JA10101>. 

Some unusual nucleophile functional groups that have been utilized in cyclofunctionalizations to form bridged ring systems include cyclic hemiacetals (equation 18)73 and epoxides (equation 19).87 The cyclizations in equation (20) involve a cyclic enol ether as the reactive ir-system and have been used in syn-... 

Various nucleophiles, such as alcohols, fluoride ion, amides, allylsilane, and electron-rich aromatic rings, have been successfully used in this reaction in either an inter- or intra-molecular mode. A recent example of a new C-C bond formation in this reaction in the inter-molecular mode includes the preparation of derivatives 17 by the oxidation of 2-alkoxynaphthols 16 in the presence of an allylsilane or a silyl enol ether as a carbon-based nucleophile (Scheme 7) [22]. 

In modern organic chemistry, silyl enol ethers, as well as the corresponding titanium, tin, boron, or zirconium derivatives, are widely employed as nucleophilic components in enolate alkylation reactions. Their usefulness prompted the elaboration of numerous methods for the selective production of isomeri-cally pure enol ethers from almost any type of carbonyl compounds. 

Compounds with an additional 2-vinyl group, easily available in two steps from a,J -unsaturated ketones, are of special interest. If the reactive vinyl ketone moiety is liberated, it can be trapped in situ by suitable nucleophiles, e.g. CH-acids, generating polyfunctional compounds or by a diene unit which undergoes an intramolecular Diels-Alder reaction (equation 93). Besides, radical additions to the vinylcyclopropane are also possible giving silyl enol ethers as ring-opened products . Future synthetic applications of theses processes are obvious. 

Michael reaction.Using enones as acceptors, enol silyl ethers as nucleophiles, and a chiral BINOL-TiO catalyst, the Michael reaction takes place at —78°C. The ee Nalues range from moderate to highly respectable (36-90%). 

A review of the Pummerer reaction describes much of the breadth of this work [18], but a more recent paper expanded this chemistry to form spirocycles which contain adjacent quaternary carbons [20]. While the test cases (22 to form the spirocycle 23) proceeded smoothly, the application to a more complicated structure (24), which would be closer to the ring system seen in the natural product, crassanine, demonstrated that a nearby amine would interfere with the addition of the silyl enol ether as a nucleophile. While this precludes the utility of this reaction for the crassanine alkaloids, the unusual ring formed in 25, a C-3-azetidine spirocyclic indolenine, is found in the chartelline alkaoids. 

While the diastereoselective cleavage of cyclic chiral acetals is quite well established [108-110], enantioselective variants, e.g., desymmetrizations of me o-acetals [Eq. (7)], are much less reported. The group of Harada used chiral aryl-boron Lewis acids for the enantioselective ring cleavage of 1,3-dioxolanes by si-lyl enol ethers as carbon nucleophiles [111, 112]. 

Methylene-l,3-diol esters have been less studied, but they produce interesting results summarized in Scheme 42. /3-Ketoesters afford six-membered cyclic enol ether as shown by Malacria and co-workers However, Buono and Tenaglia have studied stabilized nucleophiles possessing only one intercarbonilic proton. In these cases the carbon atom in alpha position to only one carbonyl group acts as second nucle-ophile.P " ... 

We investigated an interaction of 2-acyl( clohexane-l,3-diones la-c containing a perfluoroalkylated side chain with o-phenylenediamine. A direct reaction of the latter with o-phenylenediamine produees a mixture of acid cleavage products, as reported for their aeyelie analogues [7], As an alternative approach to the synthesis of perfluoroalkylated dibenzo[b,e][l,4]diazepinones, an interaction of enol ethers of 2-perfluoroalkanoylcyclohexane-l,3-diones la- c with o-phenylenediamine is proposed, beeause of an advanced reactivity of enol ethers to nucleophilic reagents versus the initial cyclic P,P -triketones [8],... 

The stereoselectivity in TiCU-promoted reaction of silyl ketene acetals with aldehydes may be improved by addition of Triph-enylphosphine (eq 12). Enol ethers, as well as enol acetates, can be the nucleophile (eqs 13 and 14). 2-Acetoxyfuran, in analogy to vinyl acetates, reacts with aldehydes to furnish 4-substituted butenolides under the influence of TiCU (eq IS). ... 

The formation of the above anions ("enolate type) depend on equilibria between the carbon compounds, the base, and the solvent. To ensure a substantial concentration of the anionic synthons in solution the pA" of both the conjugated acid of the base and of the solvent must be higher than the pAT -value of the carbon compound. Alkali hydroxides in water (p/T, 16), alkoxides in the corresponding alcohols (pAT, 20), sodium amide in liquid ammonia (pATj 35), dimsyl sodium in dimethyl sulfoxide (pAT, = 35), sodium hydride, lithium amides, or lithium alkyls in ether or hydrocarbon solvents (pAT, > 40) are common combinations used in synthesis. Sometimes the bases (e.g. methoxides, amides, lithium alkyls) react as nucleophiles, in other words they do not abstract a proton, but their anion undergoes addition and substitution reactions with the carbon compound. If such is the case, sterically hindered bases are employed. A few examples are given below (H.O. House, 1972 I. Kuwajima, 1976). 

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