Electrophilic activation of carbonyl compounds

Maruoka reported the use of the didentate catalyst 8 for double electrophilic activation of carbonyl compounds [70], but since no comparison with monofunctional phenolates was given it is not clear whether having two aluminium centres in the same catalyst offers any special advantages. They used this catalyst to effect transfer hydrogenation between remote aldehyde and alcohol groups in the same molecule [71], but again it is not clear whether the transfer is truly intramolecular or in any way different from that of reduction by an external alcohol using 8 or a monuclear aluminium catalyst. 

ZnBr2 also is an effective catalyst for the carbonyl insertion (Equation (75)).290 The Zn-catalyzed reaction is applicable to various aldehydes and ketones including aliphatic compounds. In sharp contrast to the Cu-catalyzed reaction, the carbonyl insertion occurs on the less substituted side with high regioselectivity. ZnBr2 most likely serves as electrophilic activation of carbonyl compounds. 

Recently, a new effective method for electrophilic activation of carbonyl compounds was proposed in order to enable the latter to react with weak nucleophiles such as nitriles102. This method involves the conversion of aldehydes and ketones into highly active acyloxycarbenium ions 163. This new type of carboxonium ions is related to the hydroxycarbenium and alkoxycarbenium ions 105, whose high stability is well known76. 

Maruoka et al. have developed the aluminum-based bidentate Lewis acid 14 for double electrophilic activation of carbonyl compounds (Scheme 10.9) [37]. The aldol addition of cyclohexanone TMS enolate to benzaldehyde is effected by the bidentate 14, whereas its monodentate counterpart 15 shows no evidence of reaction under similar conditions. In competitive reactions of aldehydes and acetals, 14 effects aldehyde-selective addition [38]. 

Fig. 2.8 Three modes of electrophilic activation of carbonyl compounds.

Compared to monodentate Lewis acid (19), bidentate Lewis acid (17) resulted in higher electrophilic activation of carbonyl compounds. For example, in the presence of Lewis acid (17), BusSnH reduction of acetophenone smoothly proceeded at —78 °C to give phenylethanol in 91% yield. A similar reaction with Lewis acid (19) gave phenylethanol in only 9% yield (Scheme 6.43). 

Chiral phosphoric acids mediate the enantioselective formation of C-C, C-H, C-0, C-N, and C-P bonds. A variety of 1,2-additions and cycloadditions to imines have been reported. Furthermore, the concept of the electrophilic activation of imines by means of phosphates has been extended to other compounds, though only a few examples are known. The scope of phosphoric acid catalysis is broad, but limited to reactive substrates. In contrast, chiral A-triflyl phosphoramides are more acidic and were designed to activate less reactive substrates. Asymmetric formations of C-C, C-H, C-0, as well as C-N bonds have been established. a,P-Unsaturated carbonyl compounds undergo 1,4-additions or cycloadditions in the presence of A-triflyl phosphoramides. Moreover, isolated examples of other substrates can be electrophil-ically activated for a nucleophilic attack. Chiral dicarboxylic acids have also found utility as specific acid catalysts of selected asymmetric transformations. 

Carbonyl compounds can react with nitriles by two alternative paths (a) by an initial electrophilic activation of the carbonyl component 283 followed by reaction of the formed carboxonium ion electrophile 284 with nitrile 286 as a covalent nucleophile, and (b) by an initial electrophilic activation of the nitrile component 286 to give the cationoid electrophile 287, which then attacks the carbonyl group of 28349 forming 288 in a reaction which resembles the O-acylation by acylium ions (equation 77). 

In that way, two independent paths for the reaction of carbonyl compounds with nitriles under alternative electrophilic activation of either components have been found experimentally. Both are catalyzed by protic and Lewis acids. In this connection, the problem arises which of the two reaction mechanisms takes place. In order to solve this problem theoretical calculations on the reaction pathways have been performed. 

The reaction differs from the Ritter reaction by the two types of electrophilic activation of the reagents and by the two types of rearrangement of nitrilium 285 and carboxonium ions 288 (equation 94). Besides, this interaction proceeds at an oxidation level of two, while the Ritter reaction occurs at an oxidation level of one17. While it may be shown that A-acyliminium ions 365 can be obtained from a carbonyl compound and a nitrile via the Ritter reaction, then it is only the second step b) in a three-step process where the first step (a) is the reduction of carbonyl compound 364 to alcohol 366 and the third step (c) is an oxidative dehydrogenation of amide 369 obtained3 (equation 105). 

The a-alkylation of carbonyl compounds by their conversion into nucleophilic enoiates or enolate equivalents and subsequent reaction with electrophilic alkylating agents provides one of the main avenues for regio- and stereo-selective formation of carbon-carbon a-bonds. " Classical approaches to a-alkylation typically involve the deprotonation of compounds containing doubly activated methylene or methine groups and having p/iTa values of 13 or below by sodium or potassium alkoxides in protic solvents. Since these conditions lead to monoenolates derived from deprotonation only at the a-site of the substrate, the question of the regioselectivity of C-alkylation does not arise (however, there is competition between C- and 0-alkylation in certain cases). In more recent years, dienolates of p-dicarbonyl compounds have been utilized in -alkylations with excellent success. 

Two representative organocatalytic reaction systems can be considered for nucleophilic a-substitution of carbonyl compounds, the issue of this chapter. One involves the in situ formation of a chiral enamine through covalent bond between organo-catalyst (mainly a chiral secondary amine such as proline) and substrate (mainly an aldehyde), followed by asymmetric formation of new bond between the a-carbon of carbonyl compound and electrophile. Detachment of organocatalyst provides optically active a-substituted carbonyl compound, and the free organocatalyst then participates in another catalytic cycle (Figure 6.1a) [2]. 

Orthoesters and carbonic acid derivatives can be employed in lieu of carbonyl compounds. For example, 2,2-diethoxy-2//-chromene (178) and mediyl cyanoacetate give the 2//-chromene derivative (179 Scheme 31). (Methylthio)alkylideniminium salts (180) react with active methylene compounds under basic conditions (K2CO3 or EtsN) to give the corresponding condensation products (181 Scheme 32) 240 jjjis method is an alternative to the Eschenmoser procedure for synthesizing vinylogous lactams and urethanes. A(-Alkyl and A(-acylpyridinium salts can also serve as electrophiles in the Knoevena-gel condensation with activated methylenes. " Suitably activated nitriles (R CN) such as trichloroacetonitrile or ethyl cyanoformate react with various 1,3-dicarbonyl compounds to afford (182) in the presence of catalytic amounts of metal acetylacetonates [M(acac)n]. In the presence of TiCU non-... 

Like monoheteroatomic five-membered aromatic heterocycles with inbuilt 2,5 disposed electron-rich sites, indoles and benzofurans having 2,7 positions activated towards electrophiles such as carbonyl compounds, constitute precursors for performing direct syntheses of calix[/j]indoles and calix[ ]benzofurans. These hetero-cahxarenes provide aromatic 7t-electron-rich cavities. 

The activation of electrophiles by means of Bronsted acids is a central topic in organic chemistry as it allows the energy of the lowest unoccupied molecular orbital to be reduced, activating the electrophile towards a nucleophilic attack. This behaviour explains why many organic reactions of carbonyl compounds are performed in the presence of catalytic amounts of strong protic acids. 

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