Ketones as Nucleophiles

Larock has developed an effective gold(III)-catalyzed method for the conversion of 2-(l-alkynyl)-2-alken-l-ones to substituted furans [28]. As an example, treatment of cyclohexenone 15 with methanol and a catalytic amount of AUCI3 in dichloromethane at room temperature for 1 h led to isolation of furan 16 in 88% yield (Eq. (12.10)). Liang has demonstrated the suitability of ionic liquids as solvents for this transformation [29]. 

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Propadienyl phenyl sulfone can accept enamines of cyclic ketones as nucleophiles to afford fi,y-or a,/8-unsaturated ketones 193 and 194 as the major products [102],... 

Three years after the discovery of the asymmetric BINOL phosphate-catalyzed Mannich reactions of silyl ketene acetals or acetyl acetone, the Gong group extended these transformations to the use of simple ketones as nucleophiles (Scheme 25) [44], Aldehydes 40 reacted with aniline (66) and ketones 67 or 68 in the presence of chiral phosphoric acids (R)-3c, (/ )-14b, or (/ )-14c (0.5-5 mol%, R = Ph, 4-Cl-CgH ) to give P-amino carbonyl compounds 69 or 70 in good yields (42 to >99%), flnfi-diastereoselectivities (3 1-49 1), and enantioselectivities (72-98% ee). 

In research on ketones as nucleophiles, Hashmi et al. studied the cycloisomerization of propargyl ketones. Reaction took place by nucleophilic attack of the ketone followed by aromatization to furan [28] (Scheme 8.25). 

The a-oxidation of aldehydes was later further extended to the use of ketones as nucleophiles. In order to develop this reaction into a useful process, a considerable effort was made to optimize the reaction conditions as several different problems arose these included a lower reaction rate and yields because of the formation of the di-addition product at the two enolizable carbon atoms and lower 0/N-selectivity. Hayashi et al. [16a] and Cordova et al. [16c] partly solved these problems by using a relatively large excess of ketone and by applying the slow addition method leading to good chemical yields (44-91%), with near-enantiopure products being obtained (96-99% ee). 

The simplest explanation of this result is that the chemical reaction has followed essentially the same course as the biological one. First, the hemiacetal is opened by the base to give the open-chain keto-aldehyde. Rotation about a C-C bond allows a simple aldol condensation between the enolate of the ketone as nucleophile and the aldehyde as electrophile. 

From atom economy and environmental points of view, development of a new, efficient system for Mannich-type reactions in which the parent carbonyl compounds are directly used is desirable. Remarkably, DBS A catalyzes Mannich-type reactions in a colloidal dispersion system using ketones as nucleophilic components (Scheme 15.15). ... 

A particularly difficult situation arises when combining in the same reaction the use of these rather unreactive acceptors such as enones with the incorporation of ketones as Michael donors in which the formation of the intermediate enamine by condensation with the amine catalyst is much more difficult. For this reason, the organocatalytic Michael addition of ketones to enones still remains rather unexplored. An example has been outlined in Scheme 2.22, in which it has been shown that pyrrolidine-sulfonamide 3a could catalyze the Michael reaction between cyclic ketones and enones with remarkably good results, although the reaction scope was exclusively studied for the case of cyclic six-membered ring ketones as nucleophiles and 1,4-diaryl substituted enones as electrophiles. In this system the authors also pointed toward a mechanism involving exclusively enamine-type activation of the nucleophile, with no contribution of any intermediate iminium species which could eventually activate the electrophile. Surprisingly, the use of primary amines as catalysts in this transformation has not been already considered. 

First gold-catalyzed reaction of aiienes, ketones as nucleophiles and step-wise two-fold hydroarylation... 

One would not ordinarily regard ketones as nucleophiles. An Interesting reaction occurs, though, between dialkyl- and alkyl aryl ketones and organosulfur cation radicals. The products are 3-ketoalkylsulfonium salts, the stoichiometry of whose formation follows the usual pattern (eq. 21). A variety of ketones has been used (29-31), such as acetone, butanone, methyl isopropyl... 

The scope of the Brpnsted acid-catalyzed asymmetric Mannich reaction was later extended by Gong and colleagues, which used instead of silyl ketene acetals or acetyl acetone simple ketones as nucleophiles [95]. The combination of various cycloketones, phenylamines, and aldehydes in the presence of the chiral phosphoric acid catalyst 134 or 135, respectively, afforded the corresponding anti-Mamich products in high yields with good enantioselectivities (75-98% ee)... 

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