Enol silyl ethers reaction with carbonyl compounds

Using chiral catalysts, not only various enantioselective Mukaiyama and vinylogous Mukaiyama aldol reactions have been developed but also asymmetric reactions of a,a-difluoro silyl enol ethers (1) with carbonyl compounds have been reported ... 

Silyl enol ethers, Reaction of carbonyl compounds with in situ generated BrSi(CH3)3 and triethylamine results mainly in the thermodynamic silyl ether, usually the (Z)-isomer. 

Allylation andaldol reaction. Diallylstannane and silyl enol ethers condense with carbonyl compounds to furnish homoallylic alcohols and p-hydroxy ketones, respectively. A mixture of HjO, EtOH, and toluene is a suitable reaction medium as CufOTflj is stable in water. 

Mukaiyama found that Lewis acids can induce silyl enol ethers to attack carbonyl compounds, producing aldol-like products.22 The reaction proceeds usually at -78 °C without selfcondensation and other Lewis acids such as TiCl4 or SnCI4 are commonly used. The requisite silyl enol ether 27 was prepared by treatment of ketone 13 with lithium hexamethyl disilazide (LiHMDS) and trapping the kinetic enolate with chlorotrimethylsilane. When the silyl enol ether 27 was mixed with aldehyde 14 in the presence of BF3-OEt2 a condensation occurred via transition state 28 to produce the product 29 with loss of chlorotrimethylsilane. The induced stereochemistry in Mukaiyama reactions using methylketones and a, -chiral aldehydes as substrates... 

Aldol condensation. Silyl enol ethers react with carbonyl acceptors to give )3-siloxy ketones and esters. As BiX, is also a catalyst for the replacement of /3-siloxy groups, prolonged reaction times can be applied to prepare /3-halo carbonyl compounds directly. The reaction is enhanced by ultrasound. 

Reaction with ei,fi-Unsaturated Sulfoxides. The reaction of TMSI with a, -unsaturated sulfoxides in chloroform at ambient temperature is a mild, efficient, and general method for the preparation of carbonyl compounds (eq 63). The proposed reaction mechanism is shown in eq 63. Formation of a strong oxygen-silicon bond is followed by reduction of the sulfur function and oxidation of iodide to iodine, the latter precipitating in chloroform. The trimethylsiloxy anion attacks the unsaturated carbon linked to the sulfur function, which leaves the substrate, allowing the formation of the sUyl enol ether species. Finally, hydrolysis converts the silyl enol ether into the carbonyl compound. ... 

On the other hand, the use of [Rh(CO)2Cl]2 as a catalyst results in ring opening of the siloxycyclopropanes 13 to the silyl enol ethers 14 with high stereoselectivity [10]. The 2-siloxyrhodacyclobutane 15a is proposed to undergo j8-elimination to give jr-allylrhodium 16a followed by reductive elimination to the silyl enol ether 14a. 1-Trimethylsiloxybicyclo[n.l.0]alkanes serve as / -metallo-carbonyl compounds via desilylation with a variety of transition metals [11]. The palladium-catalyzed reaction of the siloxycyclopropanes 17 under carbon monoxide in chloroform provides a route to the 4-keto pimelates 18. In the presence of aryl triflates, the 1,4-dicarbonyl compounds 19 are... 

Mukiayama aldol reactions between silyl enol ethers and various carbonyl containing compounds is yet another reaction whose stereochemical outcome can be influenced by the presence of bis(oxazoline)-metal complexes. Evans has carried out a great deal of the work in this area. In 1996, Evans and coworkers reported the copper(II)- and zinc(II)-py-box (la-c) catalyzed aldol condensation between benzyloxyacetaldehyde 146 and the trimethylsilyl enol ether [(l-ferf-butylthio)vinyl]oxy trimethylsilane I47. b82,85 Complete conversion to aldol adduct 148 was achieved with enantiomeric excesses up to 96% [using copper(II) triflate]. The use of zinc as the coordination metal led to consistently lower selectivities and longer reaction times, as shown in Table 9.25 (Eig. 9.46). 

Silyl enol ethers undergo reaction with carbonyl compounds promoted by Lewis acids, but especially titanium tetrachloride. The reaction is thought to proceed via a titanium chelate which inhibits the reverse aldol process and the regiochemical integrity of the starting silyl enol ether is retained (Scheme 102).373... 

This procedure illustrates a general method for the preparation of crossed aldols. The aldol reaction between various silyl enol ethers and carbonyl compounds proceeds smoothly according to the same procedure (see Table I). Silyl enol ethers react with aldehydes at -78°C, and with ketones near CTC. Note that the aldol reaction of silyl enol ethers with ketones affords good yields of crossed aldols which are generally difficult to prepare using lithium or boron enolates. Lewis acids such as tin tetrachloride and boron trifluoride etherate also promote the reaction however, titanium tetrachloride is generally the most effective catalyst. 

Highly acid sensitive a-siloxy epoxides (108 R1 = R2 = Me) are available in good to excellent yields through the epoxidation of silyl enols ethers (107) with jV-sulfonyloxaziridine (63b) <87JOC954>. Hydrolysis of (108) gave the a-hydroxy carbonyl compound (109) in good-to-excellent yield (55-95%) and represents an alternative to peracids usually used to effect this transformation known as the Rubottom reaction. With chiral nonracemic TV-sulfonyloxaziridines the ees of (109) were low (7-11% ee) because of the poor facial discrimination between the re and si faces of the silyl enol ether (Scheme 20). 

Alder reaction. Then TBAF removed TBS and led to the hydrolysis of silyl enol ether to release carbonyl group, finally the synthesis ended in two steps to generate compound 1.7.44 from intramolecular Diels-Alder reaction, with a yield of 48 %. Unfortunately, the facial selectivity given by intramolecular Diels-Alder reaction was just opposite to the natural product. 

Treatment of methoxymethyltrimethylsilane with BuTi in THF gives methoxy-(trimethylsilyl)methyllithium, and its subsequent reactions with carbonyl compounds have been reported to afford the adducts, a-methoxy-j8-hydroxyalkylsilanes 58 (Scheme 2.38). Although the initial adducts do not undergo elimination of a silyl group in situ, the corresponding enol ethers 59 are formed upon treating... 

Silyl(methoxy)benzotriazol-l-ylmethane 62 is lithiated with BuLi to give the corresponding anion, which undergoes Peterson reactions with carbonyl compounds (Scheme 2.40) [100, 101]. The products, l-(l-methoxy-l-alkenyl)benzotriazoles 63, are synthetically equivalent to an acylbenzotriazole synthon in which the carbonyl group is masked as an enol ether [102, 103]. Transformation of the alkenyl ethers into carboxyhc acids is readily achieved by treatment with zinc bromide and hydrochloric add in refluxing 1,4-dioxane [104]. 

In 1973, Mukaiyama and his co-workers reported the use of silyl enol ethers as ketone enolate equivalents. Silyl enol ethers react with aldehydes in the presence of a stoichiometric amount of TiCU as a Lewis acid (Scheme 3-78). The Lewis acid is considered to electrophilically activate aldehydes. Since this landmark discovery, many efforts have been made to improve the original protocol, especially focusing on the use of a catalytic amount of Lewis acid catalysts.A wide variety of metal complexes and nonmetallic cationic compounds is now applicable to this reaction as a catalyst. Not only aldehydes but also acetals, ketones, and imines have been extensively employed as electrophiles for the aldol reactions. The reaction generally proceeds via an acyclic transition state, in which the electron-rich double bond of enol silyl ethers approach carbonyls activated by a Lewis acid (Scheme 3-79). In most cases, acyclic transition state with an antiperiplanar orientation of reactants well accounts for observed diastereoselectivities. ... 

Preparation of o,/3-Unsaturated Carbonyl Compounds by the Reactions of Silyl Enol Ethers and Enol Acetates with Ally Carbonates... 

Although ethereal solutions of methyl lithium may be prepared by the reaction of lithium wire with either methyl iodide or methyl bromide in ether solution, the molar equivalent of lithium iodide or lithium bromide formed in these reactions remains in solution and forms, in part, a complex with the methyllithium. Certain of the ethereal solutions of methyl 1ithium currently marketed by several suppliers including Alfa Products, Morton/Thiokol, Inc., Aldrich Chemical Company, and Lithium Corporation of America, Inc., have been prepared from methyl bromide and contain a full molar equivalent of lithium bromide. In several applications such as the use of methyllithium to prepare lithium dimethyl cuprate or the use of methyllithium in 1,2-dimethyoxyethane to prepare lithium enolates from enol acetates or triraethyl silyl enol ethers, the presence of this lithium salt interferes with the titration and use of methyllithium. There is also evidence which indicates that the stereochemistry observed during addition of methyllithium to carbonyl compounds may be influenced significantly by the presence of a lithium salt in the reaction solution. For these reasons it is often desirable to have ethereal solutions... 

Silyl enol ethers are an elegant means to protect the reactive and hence labile enolate moiety [15]. At the time of reaction, the enolate group is generated as an intermediate and reacts with the carbonyl-carrying compound. 

P 55] Before synthesis, a micro-mixing tee chip micro reactor (Figure 4.85) (with two mixing tees and four reservoirs) was primed with anhydrous tetrahydrofuran (THF). A 40 gl volume of a 0.1 M solution of tetrabutylammonium fluoride trihydrate in anhydrous THF is filled into one reservoir of a micro-mixing tee chip reactor [15], 40 gl of a 0.1 M solution of 4-bromobenzaldehyde in anhydrous THF is added to a second reservoir, 40 gl of a 0.1 M solution of the silyl enol ether (masking the enolate of a carbonyl compound such as cyclohexanone) in anhydrous THF is added to a third reservoir and anhydrous TH F is filled into the fourth collection reservoir. Electrical fields of417,455,476 and 0 V cm are applied to transport the reaction species from the respective reservoirs. The reaction is carried out at room temperature. 

The crossed aldol reaction of silyl enol ethers with carbonyl compounds (Mukaiyama-aldol) was studied by Lubineau and co-workers... 

As discussed in Chapter 9, various nucleophiles can be introduced at the ortho position of nitroarenes via the VNS process. This provides a useful strategy for the synthesis of indoles. One of the most attractive and general methods of indoles and indolinones would be the reductive cyclization of a-nitroaryl carbonyl compounds (Eq. 10.54). The VNS and related reactions afford a-nitroaryl carbonyl compounds by a simple procedure. For example, alkylation of 4-fluoronitrobenzene with a lactone silyl enol ether followed by reductive cyclization leads to tryptophols (Eq. 10.55).73... 

Besides the allylation reactions, imines can also undergo enol silyl ether addition as with carbonyl compounds. Carbon-carbon bond formation involving the addition of resonance-stabilized nucleophiles such as enols and enolates or enol ethers to iminium salt or imine can be referred to as a Mannich reaction, and this is one of the most important classes of reactions in organic synthesis.104... 

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