Carbonyl compounds Mukaiyama aldol reaction

P-hydroxy carbonyl compound Mukaiyama aldol reaction... 

As described in the sections above, it is well established that reactions of Lewis acid-activated aldehydes and ketones with silyl enolates afford -hydroxy or /7-sil-oxy carbonyl compounds (Mukaiyama aldol reactions). Occasionally, however, ene-type adducts, that is /-siloxy homoallyl alcohols, are the main products. The first example of the carbonyl-ene reaction of silyl enolates was reported by Snider et al. in 1983 [176]. They found that the formaldehyde-MesAl complex reacted smoothly with ketone TMS enolates to give y-trimethylsiloxy homoallyl alcohols in good yield. Yamamoto et al. reported a similar reaction of formaldehyde complexed with methylaluminum bis(2,6-diphenylphenoxide) [177]. After these early reports, Kuwajima et al. have demonstrated that the aluminum Lewis acid-promoted system is valuable for the ene reactions of several aldehydes [178] and for-maldimine [179] with silyl enolates bearing a bulky silyl group. A stepwise mechanism including nucleophihc addition via an acyclic transition structure has been proposed for the Lewis acid-promoted ene reactions. 

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

The crossed aldol reaction of silyl enol ethers with carbonyl compounds (Mukaiyama aldol) was first studied by Lubineau and coworkers in aqueous solvents. Without any acid catalyst, these reactions took several days to complete. A major development was the use of water-tolerant Lewis acids for such reactions, pioneered by Kobayashi and coworkers. ... 

Chiral salen chromium and cobalt complexes have been shown by Jacobsen et al. to catalyze an enantioselective cycloaddition reaction of carbonyl compounds with dienes [22]. The cycloaddition reaction of different aldehydes 1 containing aromatic, aliphatic, and conjugated substituents with Danishefsky s diene 2a catalyzed by the chiral salen-chromium(III) complexes 14a,b proceeds in up to 98% yield and with moderate to high ee (Scheme 4.14). It was found that the presence of oven-dried powdered 4 A molecular sieves led to increased yield and enantioselectivity. The lowest ee (62% ee, catalyst 14b) was obtained for hexanal and the highest (93% ee, catalyst 14a) was obtained for cyclohexyl aldehyde. The mechanism of the cycloaddition reaction was investigated in terms of a traditional cycloaddition, or formation of the cycloaddition product via a Mukaiyama aldol-reaction path. In the presence of the chiral salen-chromium(III) catalyst system NMR spectroscopy of the crude reaction mixture of the reaction of benzaldehyde with Danishefsky s diene revealed the exclusive presence of the cycloaddition-pathway product. The Mukaiyama aldol condensation product was prepared independently and subjected to the conditions of the chiral salen-chromium(III)-catalyzed reactions. No detectable cycloaddition product could be observed. These results point towards a [2-i-4]-cydoaddition mechanism. 

The Mukaiyama aldol reaction can provide access to a variety of (3-hydroxy carbonyl compounds and use of acetals as reactants can provide (3-alkoxy derivatives. The issues of stereoselectivity are the same as those in the aldol addition reaction, but the tendency toward acyclic rather than cyclic TSs reduces the influence of the E- or Z-configuration of the enolate equivalent on the stereoselectivity. 

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 ... 

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... 

Because these asymmetric aldol reactions are ideal methods for constructing (3-hydroxy carbonyl compounds in optically active form, the development of an asymmetric aldol reaction without the use of an organostannane would be advantageous. Yamagishi and coworkers have reported the Mukaiyama aldol reaction using trimethylsilyl enol ethers in the presence of the BINAP-AgPF6 complex to afford the adducts with moderate enantioselectivities (Table 9.9).18 They have also assigned... 

In 1995 Carreira et al. [19] reported a catalytic variant of the asymmetric carbonyl-ene reaction (Scheme Ha). By treatment of the aldehyde 60 with 2 mol % of titanium catalyst 35, already used in the Mukaiyama aldol reaction, the / -hy-droxyketone 61 is formed in quantitative yield and with an excellent ee value. Here, the ene-compound, 2-methoxypropene, is used simultaneously as solvent in a large excess. The high en-antioselectivity is still limited to aldehydes similar to 60 benzaldehyde for instance is converted with an ee of only 66 %. 

The directed aldol reaction is an important means of selective carbon-carbon bond formation. This reaction is efficiently achieved by the transformation of one carbonyl group to a silylated enol derivative, which subsequently couples with another carbonyl compound with the aid of a Lewis acid, typically TiCl4, as formulated in Eq. (2). This type of directed aldol reaction is called the Mukaiyama aldol reaction, a standard and practical synthetic protocol with broad application which has, accordingly, been reviewed extensively [38-42] in addition to the reviews cited in the introductory section. The fundamental reactions between enol silyl ethers and an aldehyde or a ketone... 

There are two different modes of cyclizations in hetero [4+2] cycloadditions involving Danishefsky s diene 1) concerted (pericyclic) and 2) stepwise. When carbonyl compounds are reacted with Danishefsky s diene, the stepwise pathway is often referred to as the Mukaiyama aldol reaction pathway. The concerted process is called the Diels-Alder pathway. The mode of cyclization in the case of Lewis acid catalyzed reactions depends on the Lewis acid itself and whether it is present in stoichiometric or catalytic amounts. The Mukaiyama aldol pathway has been... 

Mukaiyama aldol reaction Lewis acid mediated addition of enol silanes to carbonyl compounds. 298... 

Conjugate additions. Cyclopentaneacetic esters are readily prepared by cyclization of -iodo-a,P-unsaturated esters. The Michael reaction of silyl ketene acetals with enones (and Mukaiyama aldol reaction) can be promoted by Sml,. " However, thermodynamic enolsilylation of carbonyl compounds under similar conditions is noted. 

Various reactions. The binary salt is a very useful reagent for promoting Barbier reaction, Mukaiyama-aldol reaction, Michael reaction, Mannich reaction, Diels-Alder reaction, as well as the reductive coupling of carbonyl compounds and of imines. 

Cyanohydrins. The organotin compound catalyzes the Mukaiyama aldol reaction, the derivatization of carbonyl compounds with MejSiCN, and other Lewis acid-catalyzed processes at -78°. It is prepared from diallyltin dibromide by reaction with pentafluorophenylmagnesium bromide followed by bromolysis. 

As a result of the preliminary examples described in Sect. 3.1 and the quest for automation techniques in solution-phase synthesis, various examples of continuous flow processes appeared in the literature lately which utilized solid-phase-bound chemical catalysts. In a simple example, Yamamoto and coworkers studied the use of super Bronsted acids loaded on polystyrene beads 5 for use in a single-pass column system (Fig. 4) [30]. It was shown that these columns are suited for the acetylation of alcohols, acetalization of carbonyl compounds, Sakurai-Hosomi allylation reactions, and Mukaiyama aldol reactions. 

Besides the aldol reaction to form y0-hydroxyketone, 1,3-Dipolar Cycloaddition can also form similar molecules. In addition to the Mukaiyama Aldol Reaction, the following are also similar or closely related to the aldol reaction the Claisen-Schmidt Condensation (the aldol reaction between benzaldehyde and an aliphatic aldehyde or ketone in the presence of relatively strong bases to form an o, )0-unsaturated aldehyde or ketone), the Henry Reaction (base-catalyzed addition of nitroalkane to aldehydes or ketones), the Ivanov Reaction (the addition of enediolates or aryl acetic acid to electrophiles, especially carbonyl compounds), the Knoevenagel Reaction (the condensation of aldehydes or ketones with acidic methylene compounds in the presence of amine or ammonia), the Reformatsky Reaction (the condensation of aldehydes or ketones with organozinc derivatives of of-halo-esters), and the Robinson Annulation Reaction (the condensation of ketone cyclohexanone with methyl vinyl ketone or its equivalent to form bicyclic compounds). 

Mechanistically related to the Mukaiyama aldol reaction, the carbonyl ene reaction is the reaction between an alkene bearing an allylic hydrogen and a carbonyl compound, to afford homoallylic alcohols. This reaction is potentially 100% atom efficient, and should be a valuable alternative to the addition of organometallic species to carbonyl substrates. However, the carbonyl ene reaction is of limited substrate scope and works generally well in an intermolecular manner only with activated substrates, typically 1,1-disubstituted alkenes and electron-deficient aldehydes (glyoxylate esters, fluoral, a,p-unsaturated aldehydes, etc.), in the presence of Lewis acids. The first use of chiral catalyst for asymmetric carbonyl ene was presented by Mikami et al. in 1989. ° By using a catalytic amount of titanium complexes prepared in situ from a 1 1 ratio of (rPrO)2titaniumX2 (X = Cl or Br) and optically pure BINOL, the homoallylic alcohols 70a,b were obtained in... 

The aldol reaction is one of the oldest and important methods for the construction of carbon-carbon bonds in organic chemistry. A classic aldol reaction is the reaction of two carbonyl compounds, or a carbonyl electrophile with an enol nucleophile, to form a new /3-hydroxy carbonyl compound. The first report was appeared in 1872 (1,2), and later in nearly 140 years, new and powerful variants of these classical aldol reactions, such as Mukaiyama aldol reactions, vinylogous aldol reactions, and reductive aldol reactions, and so on have been developed as one of the most versatile and reliable carbon-carbon bond-forming reactions in the syntheses of many important natural occurring or synthetic molecules (3-6). There now exists a large amount of literature documenting different aspects of aldol reactions, and the stable increasing is predictable. 

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