Metal-free enolate

The mechanism begins the same way as the Hg-mediated nucleophilic addition to alkenes. In the first step, an electrophilic 7r complex forms between the alkyne and Hg(II). Water attacks one of the C atoms of the ir complex in Markovnikov fashion to give a 2-hydroxy- l-alkenylmercuryfH) compound, an enol, which is pro-tonated to give a carbocation. Fragmentative loss of Hg(II) then occurs to give a metal-free enol, which tautomerizes to give the ketone product. 

Eluoride ion-catalyzed aldol reactions of silyl enolates are valuable for stereoselective carbon-carbon bond formation [19]. In this system fluoride ion works as an activator of silyl enolates to produce reactive metal-free enolates, which add to aldehydes as the actual nucleophiles. Similar aldol reactions via activation of silyl enolates by nucleophilic reagents and solvents have been reported in recent years. In addition, activation of silyl enolates by transmetalation has attracted much attention because of its possible application to diastereo- and enantioselective transformation. 

Thereafter, Yamamoto reported the first metal-free Bronsted add catalyzed asymmetric protonahon reachons of silyl enol ethers using chiral Bronsted acid 13c in the presence of achiral Bronsted add media (Scheme 5.34) [61]. Importantly, replacement of sulfur and selenium into the N-triflyl phosphoramide increases both reactivihes and enanhoselectivihes for the protonation reaction. 

In contrast, asymmetric Michael reactions are promoted by alkali metal free La-BINOL ester enolate complexes (Scheme 28) [251]. The catalyst is best prepared by successive addition of the Michael donor and (S)-BINOL to La(0 Pr)3. 

Fig. 13.17. Highly "Z"-selec-tive generation of ester enolates in a THF/DMPU solvent mixture (DMPU, /V,/V -dimethyl-propyleneurea). The transition state A of this deprotonation with a metal-free diisopropy-lamide anion (in solution) corresponds to the calculated transition state B of the deprotonation of propionic aldehyde with a hydroxide anion (in the gas phase).

TCs are well documented to bind various metal ions, including alkaline earth metals, Al(ni) and transition metals VO(II), Cr(III), Mn(II), Fe(II/III), Co(II), Ni(II), Cu(II) and Zn(II) . TC can form 2 1 TC-metal complexes with transition metal ions in non-aqueous solution, in which the metal is bound at the 2-amido and 3-enolate chelating sites . TCs are present in plasma mainly in the Ca(II)-bound form or Mg(n)-bound form to a lesser extent, when they are not bound to proteins such as serum albumin. Thus, the bioavailability of TCs should be dependent upon the physical and biochemical properties of their metal complexes instead of their metal-free form. 

It was proposed that a Lewis acid lanthanum center controls the direction of the carbonyl function and activates the enone while the sodium alkoxide forms enolate intermediates and regenerates the catalyst by hydrogen abstraction (Scheme 6). Other Ln/alkali metal combinations, including La/Li, show negligible asymmetric induction, yet give almost racemic products in excellent yield. In contrast, alkali-metal free BINOL ester enolate complexes catalyze Michael reactions with high enantioselectivities, albeit at lower temperatures. 

Ligand-metal ir bonding enhances the delocalization of electrons compared to that in the free enolate, producing some resonance stabilization. 

Metal Free Transition metal catalysts are highly effective for C—H bond activation. However, transition metal complexes are not only expensive, but also difficult to remove from the reaction products, resulting in toxicity concerns. DDQ is a well-known oxidant in organic chemistry [33]. For many years, it has been used for the oxidation of alcohols to ketones and aromatization. The first intermolecular C—C bond formation was realized by DDQ-mediated Mukaiyama-type aldol reactions [34], The reactions of electron-rich benzyl ethers and silyl enol ethers afforded 3-alkoxy-3-phenylpropionyl derivatives at ambient temperature with moderate to excellent yields (Equation 11.12). 

The aldol products formed in these reactions were found to have predominantly erythro stereochemistry, in accord with reaction via the free enolate, since it was considered that in these circumstances the repulsion between negatively charged oxygen atoms in the transition state would ensure that they were widely separated. Threo stereochemistry is by contrast realized when a metal centre maintains the oxygen atoms close together181. 

The a-heterofunctionaUsation of aldehydes and ketones can be achieved via the reaction of chiral noirracemic metal-enolates with suitable electrophiles or by activation of the electrophilic heteroatom source with an enantiomerically pure Lewis add catalyst. Alternatively, metal-free a-functionalisation can be achieved via the reversible formation of enamines and this approach has proved a successful method for the synthesis of a range of enantioenriched a-heteroaldehydes and ketones. 

Imidoiodanes, ArINTs (Section 2.1.12.4), can be used for various amidations under transition metal catalysis (Section 3.1.21) [584-586] or under metal-free conditions [587,588], In particular, o-alkoxyphenyliminoiodane 518 readily reacts with silyl enol ethers 517 in the presence of BFs-etherate to give products of a-tosylamination 519 in good yields (Scheme 3.205) [588], Furthermore, reagent 518 in the presence of catalytic amounts of iodine readily reacts with adamantane to give the product of tosylami-nation (520) in excellent yield under very mild conditions. For comparison, PhINTs reacts with adamantane and iodine (0.2 equiv) in dichloromethane at room temperature in 2 h to afford 1-tosylaminoadamantane 520 in only 63% yield [589],... 

The scope of this chapter does not allow nor attempt a comprehensive account of all developed processes to date. A detailed summary, in particular of aldol, Mannich, or ot-functionalisation reactions, can be found in excellent reviews written on the topic." Barbas and List reported an asymmetric, direct, intermolecular aldol reaction of acetones and aldehydes (Scheme 5.4), presumably via enamine formation of proline and acetone. As compared to its metal-catalysed alternatives, no preformation of the respective enolate is required, a mode of action that mimics metal-free aldolase enzymes. ... 

All of the above methods introduce the aryl group during the enantiodetermining step. An alternative strategy would be to already have the aryl group in place and to generate the tertiary stereocentre via an asymmetric protonation of an enolate complex. This was first reahsed by the pioneering work of Yamamoto in this area with the use of Lewis acid assisted chiral Bronsted acid (LBA) catalysts in the enantioselective synthesis of a-aryl cyclohexanones ((2), Scheme 4.34). Initially developed with the use of stoichiometric quantities of a BlNOL-SnCLi catalyst for the asymmetric protonation of silyl enol ethers, [63] the extensive development of this reaction has resulted in a catalytic variant with an achiral proton donor [64] and expansion of the scope to include tertiary a-aryl carboxylic acids. [65] Further improvement was made with the development of a metal free IV-triflyl thiophos-phoramide BINOL derived proton source (126) [66] and more recently a Lewis base-tolerant chiral LBA [67]. 

Metal-free bisoxazolines catalyzed Diels-Alder reaction of A-substituted maleim-ides 137 with anthrone 136 derivatives was achieved by Gbbel, et al. Scheme 3.45 [61]. With the photoelectron spectra and other studies, the Br0nsted-base catalysis is assumed to be involved with formation of an ion pair between the protonated catalyst 138 and the anthrone enolate, acting as diene. 

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