Additions Reactions with Aldehydes and Ketones

A variety of electrophilic catalysts promote the addition of allylic silanes to carbonyl compounds.86 The original catalysts included typical Lewis acids such as TiCl4 or BFj.87 This reaction is often referred to as the Sakurai reaction. 

These reactions involve activation of the carbonyl group by the Lewis acid. A nucleophile, either a ligand from the Lewis acid or the solvent, assists in the desilylation step. 

Various other Lewis acids have been explored as catalysts, and the combination InCl3-(CH3)3SiCl has been found to be effective.88 The catalysis requires both components and is attributed to assistance from O-silylation of the carbonyl compound. 

Lanthanide salts, such as Sc(03SCF3)3, are also effective catalysts.89 

Silylating reagents such as TMSI and TMS triflate have only a modest catalytic effect, but the still more powerful silylating reagent (CH3)3SiB(03SCF3)4 does induce addition to aldehydes.90 

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In the aldol reaction, we saw an enolate anion acting as a nucleophile leading to an addition reaction with aldehydes and ketones. 

The reactions of 2-lithio- and 2-sodio-imidazoles and -benzimidazoles are not particularly novel. The compounds do, however, prove a means of introducing a variety of functional groups into the 2-position of the heterocyclic ring. Such metalation reactions at C-2 can only occur readily when there is no alternative site for the metal. Therefore, only N-substituted imidazoles are of synthetic utility, and it may be necessary to select an N-substituent which can be removed later. For this reason, benzyl (removed by reductive or oxidative methods), benzenesulfonyl (removed by ammoniacal ethanol), trityl (hydrolyzed by mild acid treatment) and alkoxymethyl (easily hydrolyzed in acid or basic medium) groups have proved useful in this context. A typical reaction sequence is shown in Scheme 136 <78JOC438l, 77JHC517). In addition, reactions with aldehydes and ketones (to form alcohols), with ethyl formate (to form the alcohol) and with carbon dioxide (to form carboxylic acids) have found application (B-76MI40701). 

Evans et al. recently reported the use of structurally well-defined Sn(II) Lewis acids for the enantioselective aldol addition reactions of a-heterosubstituted substrates [47]. These complexes are readily assembled from Sn(OTf)2 and C2-symmetric bis(oxazoline) ligands. The facile synthesis of these ligands commences with optically active 1,2-diamino alcohols, which are themselves readily available from the corresponding a-amino acids. The Sn(II)-bis(oxazoline) complexes were shown to function optimally as catalysts for enantioselective aldol addition reactions with aldehydes and ketone substrates that are suited to putatively chelate the Lewis acid. For example, use of 10 mol % Sn(II) catalyst, thioacetate, and thiopropionate derived silyl ketene acetals added at -78 °C in dichloromethane to glyoxaldehyde to give hydroxy diesters in superb yields, enantioselectivity, and diastereoselectivity (Eq. 27). The process represents an unusual example wherein 2,3-ant/-aldol adducts are obtained stereoselec-tively. 

P-Hydroxy selenides are conveniently prepared from epoxides by treatment with sodium phenylse-lenide (Scheme 32) and by the addition of benzeneselenenic acid and its derivatives to alkenes (Scheme 33), - -" although in some cases these reactions are not regioselective. Useful phenylseleno -etherification and -lactonization reactions have been developed which can be regioselective (equation 42 and Schemes 34 and 35). -" " Selenide- and selenoxide-stabilized carbanions have been used in addition reactions with aldehydes and ketones, - and the reduction of a-seleno ketones also provides a route to P-hydroxy selenides. ... 

Alcohols also undergo reversible addition reactions with aldehydes and ketones. The product of addition of one mole of alcohol to an aldehyde or ketone is referred to as a hemiacetal or hemiketal, respectively. Dehydration and addition of a second mole of alcohol gives an acetal or ketal. This second phase of the process can be catalyzed only by acids, since a necessary step is elimination of hydroxide ion from a tetrahedral intermediate. There is no low-energy mechanism for base assistance of this elimination step. For this reason, acetals and ketals are stable toward hydrolysis in alkaline aqueous solution. 

Enolate anions react as nucleophiles. They give nucleophilic acyl addition reactions with aldehydes and ketones. The condensation reaction of an aldehyde or ketone enolate with another aldehyde or ketone is called an aldol condensation. Selfcondensation of symmetrical aldehydes or ketones leads to a single product under thermodynamic conditions. Condensation between two different carbonyl compounds gives a mixture of products under thermodynamic conditions, but can give a single product under kinetic control conditions. 

The a-proton of an aldehyde or ketone is less acidic as more carbon substituents are added. As more electron-withdrawing groups are added, the a-proton becomes more acidic, so a 1,3-diketone is more acidic than a ketone. The more acidic proton of an unsymmetrical ketone is the one attached to the less substituted carbon atom 8,12,13,14,22,23,28,30, 77,81,86,89,93. Enolate anions react as nucleophiles. They give nucleophilic acyl addition reactions with aldehydes and ketones. The condensation reaction of an aldehyde or ketone enolate with another aldehyde or ketone is called an aldol condensation. Selfcondensation of symmetrical aldehydes or ketones leads to a single product under thermodynamic conditions. Condensation between two different carbonyl compounds gives a mixture of products under thermodynamic conditions, but can give a single product under kinetic control conditions 5, 9, 11, 15, 16, 17, 18,19,20,21,23,29,30,31,32,33,34,40,41,42,43,44,45,46,49,91, 92, 94,102,114,115,123,134. 

Reactions with Aldehydes and Ketones. The base-catalyzed self-addition of acetaldehyde leads to formation of the dimer, acetaldol [107-89-1/, which can be hydrogenated to form 1,3-butanediol [107-88-0] or dehydrated to form crotonaldehyde [4170-30-3]. Crotonaldehyde can also be made directiy by the vapor-phase condensation of acetaldehyde over a catalyst (53). 

Issleib, Oehme, and Zschunke [72MI1 73ZC(13)291 78PS(5)81 79ZC57] obtained secondary phosphines with a y-oxypropyl substituent via the addition of primary phosphines to allyl alcohols and studied their reactions with aldehydes and ketones. Addition of carbonyl compounds proceeds without catalysts at room temperature and is accompanied by... 

Dihydro derivatives are readily formed in reactions with aldehydes and ketones, and aldehyde addition products can be dehydrogenated to the fully conjugated heterocycles <1981RCR816, 1995AQ151>. In a new procedure, palladium iodide-catalyzed carbonylation of 1,8-naphthalenediamine 918 gave 2(l//)-perimidinone 921 in 91% yield <2004JOC4741>. 

The earliest studies on allenylzinc reagents were mainly concerned with the regioselec-tivity of addition reactions to aldehydes and ketones. Moreau and Gaudemar converted... 

Reactions with Aldehydes and Ketones. Alcohols may combine additively with other carbonyl compounds such addition compounds are known as hemiacetals or acetals (Reaction XVII). 

Organolithium reagents reacts just like Grignard reagents. For example, reaction with aldehydes and ketones proceeds by nucleophilic addition to yield secondary and tertiary alcohols respectively. 

The reactions in this chapter begin with the addition of a nucleophile to the carbon of a carbonyl group and an electrophile, usually a proton, to the oxygen. Under basic conditions the nucleophile adds first, whereas the proton adds first under acidic conditions. Depending on the nature of the nucleophile, the reaction may stop at this stage or proceed further. Figure 18.7 summarizes the mechanisms followed by the various nucleophiles. Table 18.2 lists the nucleophiles and the products that result from their reactions with aldehydes and ketones. 

The reaction of a silylacetate derivative with an aldehyde or ketone was initially studied by Rathke and Yamamoto. Rathke and coworicers studied the addition of the lithium anion of r-butyl (trimethylsi-lyl)acetate (340) with a variety of aldehydes and ketones (equation 78). The anion can be formed directly from the silyl compound on treatment with LDA. The reaction proceeded to give the conjugated alkenes in excellent yields. Unsaturated compounds reacted via 1,2-addition. No discussion of alkene geometry was present. In the Yamamoto work, the ethyl (trimethylsilyl)acetate derivative (342) was used in a variety of reactions with aldehydes and ketones (equation 79). The anion was formed wiA dicyclohexyl-amide in THF. It was stated in the experimental section that the ( ) (Z) ratios of alkenes were dependent on the reaction conditions. In all the examples presented in this work, the ( )-isomer was predominantly formed. 

In accordance with the above discussion, general base catalysis is not found in thiol addition reactions to aldehydes and ketones only specific base catalysis is prevalent (Lienhard and Jencks, 1966). This is in contrast to the general base-catalyzed hydration of ketones or aldehydes. The reactions of the carbonyl group at the carboxylic acid level of oxidation have much in common with the reactions of the carbonyl group at the aldehyde or ketone level of oxidation. In an excellent review on simple carbonyl addition reactions Jencks (1964) has discussed in detail the mechanisms of catalyzed additions to the carbonyl group of ketones and aldehydes. For general base-catalj ed additions the mechanism... 

There are many regiospecific reactions with aldehydes and ketones, such as the four-membered ring example 110 which gives an addition to the aldehyde 111 very like the aldol reaction with a silyl enol ether (and even uses the same catalyst, TiCI4) to give the unsaturated alcohol32 112 - presumably the key step is 113. 

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