Electrophilicity of aldehydes

In the presence of 168 a (9mol%) and a phosphine oxide (Bu),P(O) and Ph2P(O)Me for aromatic and ahphatic aldehydes, respectively, 36 mol%), slow addition of TMSCN achieves excellent enantioselectivity with a wide range of aldehydes (86-100%, 83-98% ee). The Al complex has been proposed to work as a bifunctional catalyst for dual activation of the two reactants - the Lewis acidic Al center enhances the electrophilicity of aldehydes and the Lewis basic phosphine oxide induces cyanide addition by nucleophihc activation (Scheme 10.240). This catalytic asymmetric cyanosilylation has been used for the total synthesis of epothilones [652]. 

Pyrroles react with the conjugate acids of aldehydes and ketones to give carbinols (e.g. 67) which cannot normally be isolated but which undergo proton-catalyzed loss of water to give reactive electrophiles (e.g. 68). Subsequent reaction may lead to polymeric products, but in the case of reaction of pyrrole and acetone a cyclic tetramer (69) is formed in high yield. 

Asymmetric electrophilic substitution of aldehydes and ketortes via (S) or (R)-1-amino-2-methoxymethylpyrrolldine (SAMP or RAMP) hydrazones. 

Fluorocylatwn of enarnines and enamides has been intensively studied by different groups [78, 79, 80 SI] The effectiveness of this particular electrophilic substitution reaction becomes obvious when the nitrogen atom of the enamine moiety is engaged in an aromatic system [82 S3] or when the olefinic system is part of an aromatic nucleus [84] (equations 37 and 38) A further extension of this reaction is demonstrated by the tnfluoracetylation of aldehyde dialkyl hydrazones [S5 86] (equation 39)... 

The most common reaction of aldehydes and ketones is the nucleophilic addition reaction, in which a nucleophile, Nu , adds to the electrophilic carbon of the carbonyl group. Since the nucleophile uses an electron pair to form a new bond to carbon, two electrons from the carbon-oxygen double bond must move toward the electronegative oxygen atom to give an alkoxide anion. The carbonyl carbon rehybridizes from sp2 to sp3 during the reaction, and the alkoxide ion product therefore has tetrahedral geometry. 

As we saw in A Preview of Carbonyl Compounds, the most general reaction of aldehydes and ketones is the nucleophilic addition reaction. A nucleophile, Nu-, approaches along the C=0 bond from an angle of about 75° to the plane of the carbonyl group and adds to the electrophilic C=0 carbon atom. At the same time, rehybridization of the carbonyl carbon from sp2 to sp3 occurs, an electron pair from the C=0 bond moves toward the electronegative oxygen atom, and a tetrahedral alkoxide ion intermediate is produced (Figure 19.1). 

The condensation of 2,5-diunsubstituted pyrroles with formic acid20 is a viable method to produce porphyrins. However, the most common procedure21 22 involves the heating of the corresponding pyrroles 1 with aldehydes and aldehyde derivatives like imines or a Mannich reagent in the presence of acid. The reaction is initiated by electrophilic attack of the aldehyde (or aldehyde derivative) to the pyrrole 1. The formed (hydroxyalkyl)pyrrole 3 then undergoes electrophilic substitution with another pyrrole to form a dipyrrylmethane 4. Repeated addition of aldehyde and pyrrole finally forms a tetrameric (hydroxyalkyl)bilane 5. 

The oxidation of aldehydes to carboxylic acids can proceed by a nucleophilic mechanism, but more often it does not. The reaction is considered in Chapter 14 (14-6). Basic cleavage of (3-keto esters and the haloform reaction could be considered at this point, but they are also electrophilic substitutions and are treated in Chapter 12 (12-41 and 12-42). 

The imide nitrogen atom was also most reactive to a variety of electrophilic species (hydrogen halides, pseudohalogens, and alkyl halides) in the parent Rimidophosphazenes, R(C—NH)-N=PPh3. With t-butyl hypochlorite the /V-chloro-derivatives, R(C=NCl)-N=PPh3, were obtained. R/ -Vinyl-phenylphosphazenes have been prepared by condensation of aldehydes with active methylene compounds ... 

Another useful approach to aldehydes is by partial reduction of nitriles to imines. The reduction stops at the imine stage because of the low electrophilicity of the deprotonated imine intermediate. The imines are then hydrolyzed to the aldehyde. Diisobutylaluminum hydride seems to be the best reagent for this purpose.88,89... 

This regiochemistry is consistent with the electrophilic character of Pd(II) in the addition step. Solvent and catalyst composition can affect the regiochemistry of the Wacker reaction. Use of /-butanol as the solvent was found to increase the amount of aldehyde formed from terminal alkenes, and is attributed to the greater steric requirement of /-butanol. Hydrolysis of the enol ether then leads to the aldehyde. 

Allylic boranes such as 9-allyl-9-BBN react with aldehydes and ketones to give allylic carbinols. The reaction begins by Lewis acid-base coordination at the carbonyl oxygen, which both increases the electrophilicity of the carbonyl group and weakens the C-B bond to the allyl group. The dipolar adduct then reacts through a cyclic TS. Bond formation takes place at the 7-carbon of the allyl group and the double bond shifts.36 After the reaction is complete, the carbinol product is liberated from the borinate ester by displacement with ethanolamine. Yields for a series of aldehydes and ketones were usually above 90% for 9-allyl-9-BBN. 

Both ketals100 and enol ethers101 can be used as electrophiles in place of aldehydes with appropriate catalysts. Trimethylsilyl iodide can be used in catalytic quantities... 

The electrophilicity of silicon is enhanced in five-membered ring structures. Chloro dioxasilolanes, oxazasilolidines, and diazasilolidines react with aldehydes in the absence of an external Lewis acid catalyst.113... 

The reaction can be performed in one flask with great operational ease a mixture of an aldehyde and p-anisidine is stirred in THF for 5-10 h at 50 °C. Then, without removing the water produced, Ni(acac)2, isoprene, and Et2Zn are added in this order at room temperature. The mixture is stirred at the same temperature for the period of time indicated (Table 8). The products 57 and 58 are isolated as a mixture by column chromatograph after the usual work-up. Table 8 demonstrates the scope regarding the kind of aldehyde that encompasses not only aromatic aldehydes but also aliphatic aldehydes and even the parent formaldehyde. Despite the diminished electrophilic reactivity of aldimines, the reaction is complete at room temperature within a reasonable reaction time. The reaction of aldimines proceeds in an opposite sense of stereoselectivity to that of aldehydes and selectively provides 1,3-syn isomers 57. 

There are several new methodologies based on the Julia olefination reaction. For example, 2-(benzo[t/Jthiazol-2-ylsulfonyl)-j -methoxy-i -methylacetamide 178, prepared in two steps from 2-chloro-iV-methoxy-jV-methylacetamide, reacts with a variety of aldehydes in the presence of sodium hydride to furnish the ajl-unsaturated Weinreb amides 179 <06EJOC2851>. An efficient synthesis of fluorinated olefins 182 features the Julia olefination of aldehydes or ketones with a-fluoro l,3-benzothiazol-2-yl sulfones 181, readily available from l,3-benzothiazol-2-yl sulfones 180 via electrophilic fluorination <06OL1553>. A similar strategy has been applied to the synthesis of a-fluoro acrylates 185 <06OL4457>. 

Reactions of organometallic derivatives with ketones, which are less electrophilic than aldehydes, usually require an equimolar amount of a chiral ligand. The first catalytic enantioselective addition of an organometallic reagent, namely ZnPh2, to dialkyl and aryl alkyl ketones was reported in 1998 by Dosa and Fu (Scheme 110).288 The procedure... 

It is well known that strong electrophiles such as carbocations are reduced by organosilicon hydrides (Eq. 1).3,70,71 On the other hand, simple mixtures of organosilicon hydrides and compounds with weakly electrophilic carbon centers such as ketones and aldehydes are normally unreactive unless the electrophilicity of the carbon center is enhanced by complexation of the carbonyl oxygen with Brpnsted acids3,70 73 or certain Lewis acids (Eq. 2).1,70,71,74,75 Using these acids, hydride transfer from the silicon center to carbon may then occur to give either alcohol-related or hydrocarbon products. 

The use of trimethylsilyl-based electrophilic catalysts with organosilicon hydrides also promotes the conversion of aldehydes into ethers and avoids the need to employ the potentially hazardous trityl perchlorate salt.314,334,338 One reagent pair that is particularly effective in the reductive conversion of aldehydes into symmetrical ethers is a catalytic amount of trimethylsilyl triflate combined with either trimethylsilane, triethylsilane, PMHS,334 or 1,1,3,3-tetramethyldisiloxane (TMDO, 64) as the reducing agent (Eq. 179).314 Either... 

Two reports have been made of the preparation of P-chiral phosphine oxides through reaction of chiral f-butylphenylphosphine oxide treated with LDA and electrophiles. The electrophiles included aldehydes,355 ketones,355 and benzylic-type halides.356 Optically active a-hydroxyphosphonate products have also been generated from aldehydes and dialkyl phosphites using an asymmetric induction approach with LiAl-BINOL.357... 

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