Alkoxyketone

Buu-Hoi has shown that n-alkyl methyl ketones excluding ethyl methyl ketone, yield primarily 2-monosubstituted cinchoninic acids. It has been demonstrated that the products of the condensation of isatin with aryloxyketones are the corresponding 3-aryloxy-4-quinoline carboxylic acids rather than the isomeric 2-aryloxymethylcinchoninic acids.In the case of simple a-alkoxyketones such as 1-alkoxyethyl methylketones, the preferred products are the 2-alkoxyalkylcinchoninic... 

For ketones and aldehydes in which adjacent substituents permit the possibility of chelation with a metal ion, the stereochemistry can often be interpreted in terms of the steric requirements of the chelated TS. In the case of a-alkoxyketones, for example, an assumption that both the alkoxy and carbonyl oxygens are coordinated with the metal ion and that addition occurs from the less hindered face of this chelate correctly predicts the stereochemistry of addition. The predicted product dominates by as much as 100 1 for several Grignard reagents.120 Further supporting the importance of chelation is the correlation between rate and stereoselectivity. Groups that facilitate chelation cause an increase in both rate and stereoselectivity.121 This indicates that chelation not only favors a specific TS geometry, but also lowers the reaction barrier by favoring metal ion complexation. 

Synthesis of a-alkoxyketones from a-diazocarbonyl compounds and alcohols under the influence of copper or rhodium catalysts is well established as an alternative to the Lewis or proton acid catalyzed variant of this synthetic transformation. The sole recent contribution to the aspect of general reactivity deals with the competition between O/H insertion and cyclopropanation of unsaturated alcohols 162). The results... 

The PhSiH3/Mn(dpm)3 combination nicely reduces the conjugated C=C bond in a polyfunctional ketone without affecting the trityl group or causing reaction at the a-alkoxyketone function (Eq. 273).448... 

With conjugated enone substrates, the alkoxymetallation leads to the formation of a metal enolate that can undergo a facile protonation to accomplish the hydroalkoxylation. Following this mechanism, various /3-alkoxyketones were obtained in good yields by the addition of primary and secondary alcohols to methyl vinyl ketone under cationic Pd(n) catalysis.443 Similarly, [Rh(COD)(OMe)]2 was found to catalyze the hydroalkoxylation of both methyl vinyl ketone and phenyl vinyl ketone (Equation (121)).444... 

Alternatively, the alcohol group of the initial adducts of 119 such as 124 may be oxidized to the ketone 125 (Eq. 125). The resultant p-alkoxyketone now relieves ring... 

Trost and coworkers employed a magnesate reagent in the formal synthesis of fostriecin (Scheme 18). Stereoselective addition of the corresponding alkenylmagnesium to a-alkoxyketone proceeded smoothly in 75% yield with more than 20 1 diastereoselectivity. 

The role of titanium salt is to activate the carbonyl compounds as Lewis acid. As described above, bis(iodozincio)methane (3) is nucleophilic enough to attack the carbonyl group of aldehydes or ce-alkoxyketones. In the reaction with simple ketones or esters, however, the addition of titanium salt is necessary to facilitate the nucleophilic attack. Instead of this Lewis acid activator, simple heating may induce the nucleophilic attack. Treatment of 2-dodecanone with 3 without titanium salt at higher temperature, however, does not improve the yield of alkene (Scheme 13). The reason for the low reactivity of 3 at higher temperature comes from the structural change of 3 into the polymeric methylene zinc 4 through the Schlenk equilibrium shown in equation 740. 

Synthetic Utility. One goal of this research was to investigate new synthetic uses of organomercurials. Although the synthetic utility of this reaction has not been extensively investigated, products such as that from Reaction 16 in Table I do suggest a possible utility to organic chemists. Thus, the preparation of a-alkoxyketones should be possible by consecutive alkoxymercuration and ozonation reactions. 

Some crystal structures of chelate complexes have been reported. An O-acryloyl-lactate-TiCU complex (Fig. 3) [26,27] has rare out-of-plane (Fig. 4) coordination of the acryloyl carbonyl group to the titanium a further study has been conducted [28]. Diethyl phthalate-TiCU [29], l,2-diketone-TiCl4 [25], and achiral [24] or chiral [30] acyloxazolidinone-TiCU complexes have been reported to involve in-plane coordination as shown in Fig. 5. The /S-alkoxyketone-TiCU complex shown in Fig. 6 [31] is characterized by a rare out-of-plane coordination geometry (dihedral bond angle of... 

Ti-0-C3-C4 = 57.6 °). This out-of-plane coordination was proved by NOE experiments to persist in solution. Treatment of the diastereomeric /8-alkoxyketone with TiCU generates the titanium chelate with in-plane coordination geometry (Eq. 1) [31]. NMR study of these out-of-plane and in-plane complexes of the j8-alk-oxyketones revealed that the titanium portion in the former complex acts as a stronger Lewis acid than that of the latter [31,32]-... 

Dihydrofurans. Alkylidenecarbene formation from a-alkoxyketones is followed by C-H bond insertion. 2,8-Dioxabicyclo[3.2.1]oct-6-enes can be made this way, although such compounds are unstable. 

Synthesis of ot-alkoxyketones from a-diazocarbonyl compounds and alcohols under... 

Eliel and coworkers [94] have shown that the occurrence of chelation-control provides a corresponding rate increase in the reactions of a-alkoxyketones with Me2Mg (Figure L24). To observe chelation control and the attendant rate enhancement, the solvent should be a poor Lewis base in order not to compete with the ether substituent The ether R" substituent must not be too bulky methyl or benzyl ethers are highly reactive and selective, while trimethylsilyl ethers are less useful. Triisopropylsilyl ethers react non stereoselectively and at the lowest rate (Figure L25). 

One further insight into the coordination chemistry of these lithium enolates is obtained from the stereoselectivity observed in the reactions of chiral a-alkoxyketone enolates. For example, the... 

Reaction with carbonyl electrophiles is possible, so enantiopure stannanes are excellent precursors of enantiopure a-alkoxy tertiary alcohols [165,167], a-alkoxy acids and esters [180], and a-alkoxyketones [181], and y-alkoxyhydrazides (precur-... 

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