Silyl enol ethers Friedel-Crafts reactions

Fluoral hydrate and hemiacetals are industrial products. They are stable liquids that are easy to handle, and they react as fluoral itself in many reactions. Thus, in the presence of Lewis acids, they react in Friedel-Crafts reactions. They also react very well with organometallics (indium and zinc derivatives) and with silyl enol ethers.Proline-catalyzed direct asymmetric aldol reaction of fluoral ethyl hemiac-etal with ketones produced jS-hydroxy-jS-trifluoromethylated ketones with good to excellent diastereo- (up to 96% de) and enantioselectivities. With imine reagents, the reaction proceeds without Lewis acid activation. The use of chiral imines affords the corresponding 8-hydroxy ketones with a 60-80% de (Figure 2.49). ° ... 

Friedel-Crafts alkylation has been used in an important synthesis of aryl C-glycosides, which are potent anti-tumor agents, from glycosyl fluorides (equation 99)65 661. The reaction takes place rapidly in dichloromethane, at room temperature using a novel zirconium complex and silver perchlorate combination catalyst. A similar alkylation has been performed by replacing the aromatic compound with either a silyl enol ether or an allylic compound using silver triflate as the catalyst662,663. 

Three reactions, which were known from the literature to be catalyzed by Lewis acids were selected as test reactions. A, was the Reetz alkylation of silyl enol ethers with -butyl chloride for which titanium tetrachloride is known to be useful [52]. B, was the Diels-Alder reaction between furan and acetylenedicarboxylic ester for which aluminium trichloride is a good catalyst [53]. C, was a Friedel-Crafts acylation for which aluminium trichloride is the preferred catalyst [54]. The reactions are summarized in Scheme 6. 

A Alkylation of silyl enol ether B, Diels-Alder reaction, C, Friedel-Crafts reaction. b As a rough estimate of the kinetics, f50, which is defined as the time necessary to obtain 50% of the final yield was used. 

A Alkylation of silyl enol ether, B, Diels-Alder reaction C, Friedel-Crafts reaction. 

N-Acyliminium ion pools react with various carbon nucleophiles as summarized in Scheme 5.16. For example, allylsilanes, silyl enol ethers, Grignard reagents, and 1,3-dicarbonyl compounds serve as good nucleophiles. Aromatic and heteroaromatic compounds also react as nucleophiles with N-acyliminium ion pools to give Friedel-Crafts-type alkylation products.N-Acyliminium ions are known to serve as electron-deficient 4n components and undergo [4 -F 2] cycloaddition with alkenes and alkynes. Usually these reactions take place very quickly, and therefore N-acyliminium ion pools serve as effective reagents for flash chemistry. 

Of our three specific enolate equivalents, the lithium enolates are most similar to naked enolates most reactive and most basic. The enamines are less reactive, only weakly basic but still nucleophilic in their own right, while the silyl enol ethers are the least reactive, not basic at all, and are rather like alkenes with slightly increased nucleophilicity because of an electron-donating substituent. We have already seen that they usually need a Lewis acid for efficient reaction, just like an alkene in, say, the Friedel-Crafts reaction. 

Silyl enol ethers react with acid chlorides and Lewis acids in what is effectively a Friedel-Crafts reaction.32 Both silyl enol ethers 22 and 25 derived from the ketone 23 give regiospecific acylation with MeCOCl and TiCI4. The yields of the two 1,3-diketones 89 and 90, formed as a mixture of diastereoisomers, are excellent. 

Silyl enol ethers from aldehydes 54 and esters 57 are reagents that give clean reaction at the y-position with a variety of electrophiles 58. Acylation occurs under Friedel-Crafts conditions, and the crowded esterifying group (i-Pr)2CH in 59 ensures that reaction occurs entirely at the y-position. The product is a mixture of double bond positional isomers 61 as both are conjugated with one of the carbonyl groups. 

Michael reaction of an oc,p-unsaturated ketone with a silyl enol ether (Scheme 26) and a Diels-Alder reaction of an oxazolidinone derivative with cy-clopentadiene (Scheme 27) also worked well using MC Sc(OTf)3. Moreover, a Friedel-Crafts acylation proceeded smoothly to produce an aromatic ketone in a good yield (Scheme 28). Friedel-Crafts alkylation and acylation reactions are fundamental and important processes in organic synthesis as well as in indus-... 

Silyl enol ethers (CHj = CROSiMe3) react with cyanuryl chloride and replace only one chlorine with a carbon substituent (CH2COR R = cyclopropyl, 70 /o, R = Ph, 90 /o). Friedel-Crafts arylation <83KGS1125,92EUP497734>, the Ullmann reaction of 2-iodo-1,3,5-triazine to form 2,2 -bis-1,3,5-triazine <82NKK1425>, and a palladium-catalyzed cross-coupling reaction of 2-substituted 4,6-dichloro-... 

Titanium tetrachloride is a moisture-sensitive, highly flammable liquid reacting violently with water (34). It is a strong Lewis acid capable of promoting Diels-Alder reactions (35) and induces the addition of silyl enol ethers and allyl silanes to carbonyl compounds and derivatives (34r-36). It is a less commonly used catalyst in Friedel-Crafts reactions but very useful for the acylation of activated alkenes and in the Fries rearrangement. 

The area of reactions of phosphate derivatives has been dominated by highly stereoselective reactions in which the latter were used as chiral catalysts or achiral reagents. Among this group of reactions, it is worthy to note several asymmetric reactions ring opening of w 50-aziridinium and episulfonium ions, addition of alcohols to imines, 1,3-dipolar addition of aldehydes, amino esters and dipolarophiles, protonation of silyl enol ethers, epoxidation of a,p-unsaturated aldehydes, aza-ene-type reactions as well as asymmetric versions of named reactions Mannich, Friedel-Crafts, Kabachnik-Fields, aza-Darzens and aza-Henry. 

While effective methods for regiospecific conversion of silyl enol ethers such as 10 to enolate 9 (eq 3) further extended synthetic options using these basic intermediates, the observation that electrophilic reactions of silyl enol ethers (Friedel-Crafts-type chemistry via the intermediacy of siloxonium ion 11) were highly general enabled a new array of synthetic opportunities for carbonyl functionalization, often under essentially neutral conditions. ... 

Cyclopropyl ketones can be synthesized directly from silyl enol ethers by addition of acid chlorides to a reaction mixture of Simmons-Smith reagent and the enol ether (Scheme 3). In this reaction, the Znl by-product of the cyclopropanation sequence acts as a Friedel-Crafts type catalyst to activate the acid chloride. In related studies, Grignon-Dubois and co-workers have shown that the Friedel-Crafts acylation of cyclopropyltrimethylsilanes also provides an expeditious route to cyclopropyl ketones. 

Asymmetric catalysis of Friedel-Crafts reaction with fluoral is established using chiral binaphthol-derived titanium catalysts with or without asymmetric activation to provide a practical synthetic route not only for chiral a-trifluorobenzylalcohols but so for highly enantiopure functionalized jS-trifluoroaldols through the sequential diastereoselective reactions of the resultant vinyl ethers or silyl enol ethers with electrophiles. 

Ai mmetric Friedel-Crafts Reactions of Silyl Enol Ethers a Possible Mechanism of the Mukaiyama-aldol Reactions... 

The statine-like moiety in one of the first drugs, saquinovir (23-8), comprises a transition state mimic for the cleavage of phenylalanylprolyl and tyrosylprolyl sequences. Constmction starts with the protection of the amino group of phenylalanine as its phthaloyl derivative (Phth) by reaction with phthalic anhydride this is then converted to acid chloride. The chain is then extended by one carbon using a Friedel-Crafts-like reaction. The required reagent (21-2) is prepared by reaction of the enolate obtained from the /7A-silyl ether (21-3) of glyoxylic acid and lithio... 

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