Aldol-type additions aldehydes

These results show that chemical yields are generally higher than for most aldol-type additions of ester cnolates. mainly because of the chemical activation of the methylene group by the sulfoxide, which makes this reaction suitable for any aldehyde or ketone. High asymmetric induction is also generally observed. The aldol adducts obtained by addition to aldehydes have been transformed into optically active four- and five-membered lactones38. 

Darzens reaction, the reaction between a carbonyl compound and an a-halo ester in the presence of a base, consists of an initial aldol-type addition and a subsequent intramolecular Sn2 reaction, forming an epoxide as its final product. Its high stereoselectivity thus relies on the stereoselectivity of the nucleophilic addition of an a-halo ester onto the carbonyl substrate, which can be either an aldehyde or a ketone. 

A different behavior is exhibited by naphthalene-1,8-dicarbocal-dehyde (73). No m-naphthane derivatives are obtained on reaction with nitromethane, nitroethane or other methylene components. The basic medium, required for aldol type additions, causes the dialdehyde to undergo Cannizzaro reaction to the naphthopyranon (74) via an intramolecular 1,5-hydride shift, which is sterically favoured by the peri-position of the two aldehyde functions 28). 

Open transition states have been postulated in the aldol-type additions of ( )- and (Z)-crotyl-stannanes (21/22) to aldehydes. Irrespective of the ( ) or (Z) configuration of the stannane only. yyn-adducts 23/24 are formed. Due to the Lewis acid (LA) complexation of the carbonyl oxygen, a cyclic ( closed ) transition state cannot be adopted. Instead, an open geometry is preferred, in which the methyl and the R group move apart as far as possible to generate the enantiomorphous arrangements 25/2611. 

This reaction is quite special in that it is an aldol-type addition in which a thioester is the donor (nucleophile) and a keto acid is the acceptor (electrophile). From the discussion in Section 18-8E, you will see that reactions of this kind involving an ester as the donor and an aldehyde or ketone as the acceptor can be achieved in the laboratory only under rather special conditions. For the thioester to function as a nucleophile at the a carbon under the restraints imposed by having the reaction occur at the physiological pH, the catalyzing enzyme almost certainly must promote formation of the enol form of the thioester. The enol then could add to the ketone carbonyl with the assistance of a basic group on the enzyme. This kind of catalysis by enzymes is discussed in Section 25-9C. 

As to the mechanism of benzoin formation, cyanide ion adds to the aldehyde to form 12. This anion is in equilibrium with 13, wherein the negative charge can be delocalized over the phenyl and nitrile groups. A subsequent aldol-type addition of 13 to the carbonyl carbon of a second aldehyde molecule gives the addition product 14, and loss of HCN from 14 leads to the benzoin ... 

Selective alkylation of the y position of a,/3-unsaturated esters, aldehydes, or ketones can be achieved if a sterically demanding Lewis acid is used to coordinate to the carbonyl group and inhibit a-alkylation by steric shielding [123, 125, 126] (Scheme 5.11). This method not only results in high regioselectivity but also enables highly stereoselective aldol-type additions to be performed in good yields, even with sensitive substrates, such as a,/3-unsaturated aldehydes [126]. Thus, when two dia-stereotopic y positions are available, the addition of a bulky aluminum phenolate leads to the clean formation of the Z-alkene (second and third examples, Scheme 5.11). 

Substituted 3-phenylsulfonyl-5-hydroxymethyl-THFs (e.g. 44) have been prepared chemo-, regio-, and diastereo-selectively via reaction of a y,5-cpoxycarbanion with aldehydes, RCHO.156 The initial aldol-type addition is non-diastereoselective, but reversible. The subsequent cyclization is selective, and exerts overall thermodynamic control. 

The alkylation of doubly deprotonated 6-hydroxy esters, an example of which 1s described 1n the procedure above, 1s not just a useful alternative to the diastereoselective aldol-type addition, but can supply enantiomerically pure products from appropriate precursors, and it can be used for the preparation of a/x-disubstituted derivatives (see 4 in Scheme 1). These were hitherto not available stereoselectively from enolates of a-branched esters and aldehydes. 

Another important class of compounds that undergo aldol-type additions to aldehydes and ketones is nitriles. Because nitriles can be reduced to amines, this reaction provides another useful route to 3-amino-aleohols,... 

Scheme 18). The formation can be explained by the initial conjugate umpolung of the aldehyde and subsequent 1,4-addition to the unsaturated ketone. After proton transfer, an intramolecular aldol-type addition results in the formation of the aforementioned zwitterions. Nucleophilic displacement of the imidazolium moiety by the alkoxide provides the p-laclonc, which exhibits increased strain, since it is annulated to a cyclopentane ring. Consequently, the P-lactone breaks apart and liberates CO2 and the observed cyclopentene products (Scheme 19). 

Aldol-Type Addition. Aldol-type addition of the magnesium enolate of (R)-(+)-7-butyl 2-(p-tolylsulfinyl)acetate, prepared with 7-butylmagnesium bromide, with aldehydes and ketones afforded, after desulfurization with Aluminum Amalgam, p-hydroxy esters in very high diastereoselectivity (eq Two chiral centers are created in the first step with very high diastereoselectivity (mainly one diastereomer is formed). A model M based on the structure of the sulfinyl ester enolate (determined by C NMR) and on electrophilic assistance of magnesium to the carbonyl approach, was proposed to explain and predict the absolute configuration of the two created chiral centers. ... 

The asymmetric aldol-type addition of tosylmethyl isocyanide (99) to aldehydes can also be catalyzed by the chiral silver(I) complex, giving almost exclusively trans-S-alkyl-4-tosyl-2-oxazolines 98 [E = S02(p-Tol)] with up to 86 % ee as shown in Sch. 26 [52]. The slow addition method described above is not necessary for this reaction system. 

Enol esters, like enol ethers, can also react with various acetals and aldehydes in the presence of Lewis acids such as TiCU, AlCb, SnCU, ZnCh, and BFs OEt to afford the corresponding aldol-type addition products. A typical example is the reaction of isopropenyl acetate and 7-phenylpropionaldehyde acetal... 

In this case the trityl-protected lactaldehyde 882 is prepared from trityl lactate 463 by reduction of the ester with lithium aluminum hydride followed by oxidation under Swem conditions. An aldol-type addition of titanated furan produces a 6 1 mixture of anti and syn adducts from which the pure anti diastereomer 883 is isolated by column chromatography (55% yield, >95% de). Treatment of 883 with bromine in methanol followed by acidic hydrolysis gives the ulose 885. A 1,4-reduction to 886, acetylation to 887, and ozonolysis affords the unstable aldehyde 888, which is immediately coupled with 2,5,6-triamino-4-pyrimidinol (889) to afford 890 [237]. 

Copper(II) catalysed enantioselective decarboxylative aldol-type addition of malonic acid hemithioesters to aldehydes in the presence of tartaric acid-derived bisbenzimidazole and an achiral base was examined. The use of DBU (1) as an achiral base resulted in low enantioselectivity [69]. 

Following from the examples of allyltrichlorosilanes 21.5, Denmark introduced the related eno)g4 richlorosilanes 21.97 (Scheme 21.13) to cany out Mukaiyama-lype nucleophilic additions to carbonyl compounds. " According to Mayr s nucleophilicity scale, silyl enol ethers derived from aldehydes and ketones and, in particular, silyl ketene acetals are even more powerful nucleophilic reagents than the respective allyl silanes. Indeed, the aldol-type addition of trichlorosilyl enol ethers 21.97a-d to aldehydes 21.4 proceeds readily at room temperature without a catalyst exhibiting simple first-order kinetics in each component (Scheme 21.13), which contrasts with the lack of reactivity of allyl silanes in the absence of a catalyst. 

Other Transition Metal Catalysts. The continuous search of other transition metals catalysts is not disturbed during the exploration of new catalysts for the aldol reaction. At present, the application of groups 5-7 and 12 metal as the synthetically useful catalysts for aldol reactions is only limited to vanadium and zinc. In 2001, Trost and co-workers reported a vanadium-catalyzed aldol-type addition of propargyl alcohols and allenic alcohols to aldehydes (105,106). The products are analogous to Baylis-Hillman reaction adducts (Scheme 16). 

Copper Lewis acids have also been used in decarboxylative, aldol-type additions of malonic acid hemithioesters to aldehydes. Cozzi and coworkers reported a catalyst prepared from Cu(OTf)2 and bisbenzimidazole (107) gave low to moderate yields and low enantioselectivities in additions of thioester (107) to 3-phenylpropanal or p-nitrobenzaldehyde (Scheme 17.21) [27]. 

Other reports deal with a pyrrolidine-catalysed homo-aldol condensation of aliphatic aldehydes (further accelerated by benzoic acid), a diastereoselective aldol-type addition of chiral boron azaenolates to ketones,the use of TMS chloride as a catalyst for TiCU-mediated aldol and Claisen condensations, a boron-mediated double aldol reaction of carboxylic esters, gas-phase condensation of acetone and formaldehyde to give methyl vinyl ketone, and ab initio calculations on the borane-catalysed reaction between formaldehyde and silyl ketene acetal [H2C=C(OH)OSiH3]. ... 

Chiral horane complexes (20 mol %) catalyze the aldol-type addition to achiral aldehydes in good to excellent yield and enantiomeric excess (eq... 

Thus, among the various aldehydes employed in aldol-type additions, propynal derivatives have long been neglected despite their great potential in the synthesis of antitumor antibiotics of the neocarzinostatin chromophore type (Scheme 3.68) [111]. It has been shown, however, that cobalt-complexed propynals such as 342... 

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