Mukaiyama reaction mechanism

It has been proposed that there may be a single electron transfer mechanism for the Mukaiyama reaction under certain conditions.72 For example, photolysis of benzaldehyde dimethylacetal and 1-trimethylsilyloxycyclohexene in the presence of a... 

Fig. 12.23. A Mukaiyama aldol addition (-> C) and its reaction mechanism (bottom row). As shown here, this method can be exploited to obtain the poly-unsaturated aldehyde D. Under the conditions of the first reaction step the primary product C—which, like the substrate A, is an acetal—does not compete with A for still unconsumed enol ether B. This is due to the fact that the methoxy substituent in the oxocarbenium ion G, which would have to be regenerated from Cin order to undergo further reaction with B, destabilizes G because of its electron-withdrawing inductive (-1) effect.

Although the mechanism of the Mukaiyama reaction is not yet fully understood, several points have now been firmly established (a) a Lewis acid enolate is not involved (b) the Lewis acid activates the carbonyl group for the nucleophilic addition and (c) the Si—O bond is cleaved by nucleophilic attack of the anionic species, generally halide, on silicon. Point (a) has been established by the use of INEPT- Si NMR spectroscopy. Moreover, trichlorotitanium enolates have been synthesized, characterized and shown to give a completely different stereochemical outcome than the TiCU-mediated reactions of silyl enol ethers. Complexes between Lewis acids and carbonyl compounds have been isolated and characterized by X-ray crystallography and recently by NMR spectrometry. On the basis of these observations closed transition structures will not be considered here open transition structures with no intimate involvement between the silyl enol ether and the Lewis acid offer the best rationale for the after the fact interpretation of the stereochemical results and the best model for stereochemical predictions. 

The same group of workers has proceeded to develop an intramolecular version of the reaction. The aldehyde acids (35, n = 1 or 2) on treatment with Mukaiyama s reagent, 2-chloro-l-methylpyridinium iodide, and triethylamine afforded the cis substituted bicyclic lactones (36, n = 1 or 2). The authors have adduced evidence in support of a nucleophile-catalysed aldol lactonisation (NCAL) reaction mechanism rather than the alternative thermal [2+2] cycloaddition. They have also found that the intramolecular reaction, like the intermolecular process, is subject to asymmetric catalysis. When an optically active base such as 0-acetylquinidine was present in the reaction mixture, the bicyclic lactones were produced with high ee <01 JA7945>. 

Mukaiyama et al. [44] developed an efficient method mediated by 1-methyl-2-chloropyridinium iodide and 2-chloro-6-methyl-l,3-diphenylpyridinium tetraflu-oroborate, wherein the reaction mechanism proceeds by the activation of acid followed by lactonization (Scheme 6.3). 

Finally, stereochemical aspects of the mechanism have been extensively studied by Evans and coworkers during their construction of a model to map the diastereoselective induction observed in the course of the aldol reaction. Similarly, mechanistic studies were performed by the Evans group with regards to their bis(oxazolinyl)-pyridine (pybox)-copper(II) complex, a catalyst for the enantioselective Mukaiyama reaction. ... 

The low-temperature NMR experiment implied that the catalytic reaction proceeded via the concerned [4-f2] cycloaddition pathway rather than the stepwise (Mukaiyama-aldol) mechanism. Furthermore, the phebox-Rh-catalyzed reaction proceeds via the cn fo-transition state on the basis of the c -selectivity of 11 in the reaction of 2,4-dimethyl diene with n-butyl glyoxylate (Scheme 5). The absolute configurations of the dihydropyrans proved to be 2R, indicating that the Re face attack of the diene to the C=0 group is a favorable pathway. 

As the conditions of the various Mukaiyama aldol protocols are different, the postulated mechanisms are not uniform either mostly, the activation of the carbonyl-active component by a Lewis acid is postulated. For the more recently disclosed Lewis base-induced Mukaiyama aldol versions, a nucleophilic activation of the enolate has been discussed also. Finally, transmetallation of the silicon enolate was also considered. The relevant mechanisms are treated for individual protocols of catalytic Mukaiyama reactions in Section 5.3. 

Cinchona alkaloid-derived ammonium phenoxides as Lewis base catalysts have been appUed to asymmetric vinylogous Mukaiyama-type aldol reactions (Scheme 14.8) [30]. In the first step of this reaction, silyl compound 14 reacts with ammonium phenoxide to produce ammonium dienolate 15 with generation of trimethyl(phenoxy) silane. The latter part of this reachon mechanism is basically simQar to the reaction mechanism of ammonium fluoride-catalyzed reactions with silyl nucleophiles as shown in Scheme 14.7. This reaction system was also appUed to other asymmetric transformations [6a, 31]. 

A possible mechanism of the aldol-type Mukaiyama reaction and the Sakurai allylation was investigated [98-100]. The proposed mechanism involves the catalytic activation of the aldehyde and its interaction with the silyl ketene acetal or allylsilane, resulting in an intermediate. Thereafter two possible pathways can lead either to the release of TMS triflate salt and its electrophilic attack on the trityl group in the intermediate or to the intramolecular transfer of the TMS group to the aldolate position, resulting in the evolution of the trityl catalyst and the formation of the product (Scheme 16.30). To explore both possibilities a series of experimental and spectroscopic studies were performed. 

Stereoselectivities of 99% are also obtained by Mukaiyama type aldol reactions (cf. p. 58) of the titanium enolate of Masamune s chired a-silyloxy ketone with aldehydes. An excess of titanium reagent (s 2 mol) must be used to prevent interference by the lithium salt formed, when the titanium enolate is generated via the lithium enolate (C. Siegel, 1989). The mechanism and the stereochemistry are the same as with the boron enolate. 

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 major developments of catalytic enantioselective cycloaddition reactions of carbonyl compounds with conjugated dienes have been presented. A variety of chiral catalysts is available for the different types of carbonyl compound. For unactivated aldehydes chiral catalysts such as BINOL-aluminum(III), BINOL-tita-nium(IV), acyloxylborane(III), and tridentate Schiff base chromium(III) complexes can catalyze highly diastereo- and enantioselective cycloaddition reactions. The mechanism of these reactions can be a stepwise pathway via a Mukaiyama aldol intermediate or a concerted mechanism. For a-dicarbonyl compounds, which can coordinate to the chiral catalyst in a bidentate fashion, the chiral BOX-copper(II)... 

The mechanism for the hetero-Diels-Alder reaction of benzaldehyde 9 with the very reactive diene, Danishefsky s diene 10, catalyzed by aluminum complexes has been investigated from a theoretical point of view using semi-empirical calculations [27]. The focus in this investigation was to address the question if the reaction proceeds directly to the hetero-Diels-Alder adduct 11, or if 11 is formed via a Mukaiyama aldol intermediate (Scheme 8.4) (see the chapter dealing with hetero-Diels-Alder reactions of carbonyl compounds). 

In SiCl4-mediated Mukaiyama-Michael reactions, an electron-transfer mechanism is proposed for the case in which ketene silyl acetals bearing less hindered silyl substituent are used as substrates.342-344 As shown in Scheme 82, ketene silyl acetals having more substituents at the /3-position are much more reactive. 

The most widely used method for the dehydration of primary nitroalkanes involves their treatment with phenyl isocyanate and triethylamine, introduced in 1960 by Hoshino and Mukaiyama (7). A probable mechanism for the formation of the nitrile oxide is shown in Scheme 6.4. This method is known to be very effective for the preparation of aliphatic or aromatic nitrile oxides. In some cases, the separation of the byproduct A,A -diphenylurea from the reaction mixture may be troublesome. In order to circumvent this problem, 1,4-phenylene diisocyanate was introduced (82,83). The polymeric urea that is formed as a byproduct is largely insoluble in the reaction mixture and can easily be removed. 

For a review of coupling reactions of acetals, sec Mukaiyama Murakami Synthesis 1987, 1043-1054. For a discussion of the mechanism, see Abell Massy-Wcstropp Aust. J. Chem. 1985, 38. 1031. For a list of substrates and reagents, with references, see Ref. 508, pp. 404-405. 

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