Activating the carbonyl derivative

Alkylzinc halides react only sluggishly with aldehydes or ketones. This reactivity can be improved by activating the carbonyl derivative with a Lewis acid. Excellent results are obtained with titanium alkoxides,137 Me3SiCl,138... 

A dual activation mode based on a network of hydrogen bond interactions is assumed being active in all these methodologies. In particular, the C6 —OH group could activate the carbonyl derivatives, while the quinuclidine tertiary nitrogen atom could modulate the reactivity of the hydroxybenzene (the case of Cinchona alkaloids is reported in Fig. 5.3). 

Scheme 7.91) [137]. Alkylzinc halides react only sluggishly with aldehydes or ketones. This reactivity can be improved by activating the carbonyl derivative with a Lewis acid. Excellent results are obtained with titanium alkoxides [209], McsSiCl [210] or BFj OEtj [48c] (Scheme 7.92). Depending on the nature of the catalyst either the 1,2-addition product (345) or the 1,4-addition product (346) is obtained by the addition of the zinc-copper reagent 347 to cinnamaldehyde [48c]. 

The mercuration of ferrocenylimines with Hg(OAc)2 has been studied. - 6 Mercuration occurs selectively at the a-position relative to the imine group to afford compounds 86a-i (Scheme gy107,108 The regioselectivity of these reactions points to the directing role of the Lewis-basic imine functionality. Similar factors probably play a role in the formation of the ferrocenylketone and ferrocenylaldehyde derivatives 87a-f and 87g-j, respectively. These derivatives readily react with amines to afford the corresponding imines (Scheme 9). Presumably, the Lewis-acidic mercury center of the monomercurated ferrocenylketones and ferrocenylaldehydes activates the carbonyl functionality toward nucleophilic attack by the amine. 

The Mukaiyama Reaction. The Mukaiyama reaction refers to Lewis acid-catalyzed aldol addition reactions of enol derivatives. The initial examples involved silyl enol ethers.40 Silyl enol ethers do not react with aldehydes because the silyl enol ether is not a strong enough nucleophile. However, Lewis acids do cause reaction to occur by activating the ketone. The simplest mechanistic formulation of the Lewis acid catalysis is that complexation occurs at the carbonyl oxygen, activating the carbonyl group to nucleophilic attack. 

In 1982, Sakurai [7] described a catalytic version of this reaction (Scheme 13.4). The addition of small quantities of fluoride anions to the allylsilane 1 generates the pentacoordinated silicon species 10, probably in equilibrium with the starting materials 1 and 11. This activated species can react with the carbonyl derivative 6 to yield the alkoxide 12 which is trapped by fluorotrimethylsilane. This last step not only furnishes the silylated compounds 13 but also regenerates the fluoride catalyst 11. Acidic work-up then leads to the desired homoallylic alcohol 7. 

Transition metal carbonyls and their derivatives are remarkably effective and varied in their ability to catalyze reactions between unsaturated molecules (e.g., CO and olefinic compounds) or between certain saturated and unsaturated molecules (e.g., olefins and H2 or H20). The carbonyl derivatives of cobalt are particularly active catalysts for such reactions and have been put to use in the industrial synthesis of higher aliphatic alcohols. In fact, much of the growth in knowledge concerning catalysis by metal carbonyls has been stimulated by the industrial importance of the Fischer-Tropsch synthesis, and by the economically less important, but chemically more tractable, hydroformylation reaction. 

Like acid halides, anhydrides are activated derivatives of carboxylic acids, although anhydrides are not as reactive as acid halides. In an acid chloride, the chlorine atom activates the carbonyl group and serves as a leaving group. In an anhydride, the car-boxylate group serves these functions. 

The reaction of benzyl ketones with nitriles in the presence of the phosphorus oxides is considered by Zielinski95,96 and by Garcia and coworkers97 as a variant of the Ritter reaction. This reaction leads to isoquinoline and pyrimidine derivatives. Zielinski95 supposes that phosphorus oxychloride (as well as anhydrous / -toluenesulfonic acid) activates the carbonyl group of benzyl ketone 139 for attack by the nitrile nitrogen atom (equation 47). The Af-acetyl-l-methyl-2-arylvinylamine 143 (when R2 = Me) produced in this reaction via the cationoid iminium intermediates 140, 141 and the phosphorus... 

In addition to the carbonyl derivatives, substrates such as NH-heterocycIic com-pounds or nitroalkancs have been activated as silyl derivatives. 

Boronic acids (5a) were among the first examples of low-molecular-weight, reversible inhibitors of serine proteinases [151, 152]. Significant inhibition was initially demonstrated against a-chymotrypsin. Unlike the carbonyl-derived reversible inhibitors, which require a polypeptide or peptide-like chain, activity was found with simple alkylboronic acids (e.g. the value for PhCH2CH2B(OH)2 with a-chymotrypsin was = 40 //M) [153], Weak inhibition of elastase (PPE) was first reported for a series of arylboronic acids, for example, (10-1) [123]. Some of the boron-based inhibitors Figure 2.5) were tested as either the difluoroboranes (5b) or as the pinacol boronate esters (5c). These modifications were employed because they were more readily synthesized and/or purified than the boronic acids. For both of these derivatives inhibition was shown to be due to in situ hydrolysis to the parent boronic acid (5a) [154, 155]. 

Enhanced Activity of Carbonyl Derived Catalysts for the Hydrogenolysis of Ethane... 

I n 1993, the first cinchona-catalyzed enantioselective Mukaiyama-type aldol reaction of benzaldehyde with the silyl enol ether 2 of 2-methyl-l -tetralone derivatives was achieved by Shioiri and coworkers by using N-benzylcinchomnium fluoride (1, 12 mol%) [2]. However, the observed ee values and diastereoselectivities were low to moderate (66-72% for erythro-3 and 13-30% ee for threo-3) (Scheme 8.1). The observed chiral inductioncan be explained by the dual activation mode ofthe catalyst, that is, the fluoride anion acts as a nucleophilic activator of the silyl enol ethers and the chiral ammonium cation activates the carbonyl group of benzaldehyde. Further investigations on the Mukaiyama-type aldol reaction with the same catalyst were tried later by the same [ 3 ] and another research group [4], but in all cases the enantioselectivities were too low for synthetic applications. 

TSA under solvent-free conditions to afford 1,3-dithiane and 1,3-dithiolane derivatives (Scheme 3.14). TSA is a strong solid acid that can activate the carbonyl group to decrease the energy of the transition state of the nucleophilic attack step (Karami et al., 2012i). 

The most unreactive carboxylic acid derivatives, esters and amides, usually require some form of catalysis to activate the carbonyl to nucleophilic attack. Acid catalysis for amide hydrolysis is quite effective. Since amides are so unreactive toward nucleophilic attack, specific-acid catalysis is most commonly observed. Here, full protonation of the amide carbonyl is necessary to activate the species enough that nucleophilic attack is possible (Figure 10.19 A). With acidic conditions up to about 80% acid (requiring values see Section 5.2.5),... 

Carboxylic acids, their esters, and amides are usually resistant to sodium borohydride reduction, whereas carboxylic acid chlorides may be reduced in inert solvents to give alcohols. Where this proves unsatisfactory a new alternative procedure for acid chloride reduction in ether solution involves sodium borohydride adsorbed on alumina. Other recently published borohydride reductions of acid derivatives to primary alcohols include those of the 1-succinimidyl esters (8)" and the N-nitroso-amides (9). 2-Methoxyethoxymethyl (MEM) esters have the possibility of co-ordinating the metal cation of complex hydrides at the MEM group, and hence of activating the carbonyl group towards reduction by intramolecular hydride delivery. The selective reduction of the less hindered ester group in the bis-MEM ester (10) to give (11) illustrates this idea. 

Mechanistic details of the Michael addition of CH2(CN)2 to enones RCH=CHCOPh, catalysed by the cinchona alkaloid-derived primary amines, such as (265a,b), have been illuminated by using DPT and ONIOM calculation methods (i) the acidic additive pro-tonates the quinuclidine nitrogen, which activates the carbonyl substrate by hydrogen... 

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