Carbanions addition reactions with carbonyl compounds

In this section alkylation, Michael additions, hydroxyalkylation (reaction with carbonyl compounds), aminoalkylation, acylation and some other reactions of a-sulphinyl carbanions will be discussed. 

The decarboxylation reaction usually proceeds from the dissociated form of a carboxyl group. As a result, the primary reaction intermediate is more or less a carbanion-like species. In one case, the carbanion is stabilized by the adjacent carbonyl group to form an enolate intermediate as seen in the case of decarboxylation of malonic acid and tropic acid derivatives. In the other case, the anion is stabilized by the aid of the thiazolium ring of TPP. This is the case of transketolases. The formation of carbanion equivalents is essentially important in the synthetic chemistry no matter what methods one takes, i.e., enzymatic or ordinary chemical. They undergo C—C bond-forming reactions with carbonyl compounds as well as a number of reactions with electrophiles, such as protonation, Michael-type addition, substitution with pyrophosphate and halides and so on. In this context,... 

The carbanions of 1-alkenyl sulphoxides 400 also react with carbonyl compounds to give the corresponding condensation products384 (equation 237). Solladie and Moine have used this type of reaction in their enantiospecific synthesis of the chroman ring of a-tocopherol 401. Addition of the lithio reagent 402 to the aldehyde 403 affords the allylic alcohol 404 in 75% yield as a sole diastereoisomer481 (equation 238). 

The addition reaction of enolates and enols with carbonyl compounds is of broad scope and of great synthetic importance. Essentially all of the stabilized carbanions mentioned in Section 1.1 are capable of adding to carbonyl groups, in what is known as the generalized aldol reaction. Enolates of aldehydes, ketones, esters, and amides, the carbanions of nitriles and nitro compounds, as well as phosphoms- and sulfur-stabilized carbanions and ylides undergo this reaction. In the next section we emphasize the fundamental regiochemical and stereochemical aspects of the reactions of ketones and aldehydes. 

In addition to these reactions in which the carbanions are supplied from carbonyl compounds, we will discuss in this chapter Grignard reactions, the benzilic acid rearrangement, the benzoin condensation, and the Kolbe synthesis of hydroxy aromatic acids. These reactions illustrate the addition of other kinds of carbanions to carbonyl groups. The benzilic acid rearrangement is an example of the intramolecular addition of a group with its pair of electrons to a carbonyl carbon atom. 

Although the reaction of hydroxide or alkoxide ions with carbonyl compounds to abstract a proton from a carbon atom adjacent to the carbonyl group is thermodynamically unfavourable, and the equilibria in reactions such as (4.11) and (4.12) lie well over to the left, the high reactivity of the carbanion intermediates formed makes reactions of this type of vital importance in a number of cases, especially in halogenation (reaction 4.14) and in some carbonyl addition reactions, e.g. reactions (4.20) and (4.30). 

The aldol reaction in carbonyl compounds has its equivalents in 7i-electron deficient heterocycles. In the carbanion approach, lithiated acetophenone added rapidly and regioselectively to 1-substituted 2-pyrimidinones to form the 3,4-dihydro isomer (279) (Scheme 45) <85ACS(B)195>. The adducts are readily oxidized to their aromatic equivalents (280) by DDQ. With the lithium enolate of mesityl oxide, however, equal amounts of the two dihydro isomers were formed <88JOM(338)34l>. In highly 7i-electron deficient heterocyclic systems, aldol reactions will also take place under the influence of acid catalysis such as in the addition of acetone to the pyrimidinone (281) the product is fully conjugated (282) after DDQ dehydrogenation <79ACS(B)150>. 

R,2S)-Ephedrine has found most application, e.g., as a catalyst in photochemical proton transfer reactions (Section D.2.1.). and as its lithium salt in enantioselective deprotonations (Section D.2.1.). The amino function readily forms chiral amides with carboxylic acids and enamines with carbonyl compounds these reagents perform stereoselective carbanionic reactions, such as Michael additions (Sections D.1.5.2.1. and D. 1.5.2.4.), and alkylations (Section D.1.1.1.3.1.). They have also been used to obtain chiral alkenes for [1 +2] cycloadditions (Section D. 1.6.1.5.). 

Aliphatic nitro compounds serve as good acyl anion equivalents. After electrophilic alkylation at the a-carbon atom, they can be converted into carbonyl compounds by the Nef reaction or by reductive hydrolysis with titanium(III) chloride. The a-nitro carbanions serve as excellent donors in Michael addition reactions with a, -unsaturated systems and therefore the sequence of Michael addition followed by reductive hydrolysis of the nitro group provides a good route to 1,4-dicarbonyl compounds. ds-Jasmone, for example, was readily obtained by using this strategy (1.111). 

For Michael additions of CH acidic compounds (e.g. diethyl malonate with a,3-unsaturated ketones) the following recommendations are given "When possible, relatively weak basic catalysts such as piperidine... should be selected. If stronger bases are required, it is normally appropriate to use only 0.1 to 0.3 equivalent of the base." The analogy of these conditions to those specified by our rule A is obvious (concentration control). On the other hand, preformed carbanions (organometallies) are usually employed when the addend is more basic than the enolate produced by attack at the unsaturated carbonyl compound. Though the nature of the metal ion plays a crucial rule in many "carbanionic" addition reactions, a first understanding of the principles involved can be... 

The mechanism begins with the addition of a silyl-substituted carbanion 14 to a carbonyl compound 15 an aqueous work-up then leads to a diastereomeric mixture of yff-hydroxyalkylsilanes, often isolable and sometimes separable. The stereo-selectivity of the reaction can be controlled by the steric demands of the silyl group the use of more sterically demanding silyl groups results in the erythro isomer as the major product. 

The carbonyl group of acid derivatives reacts with the nucleophilic carbanion available from organo-metallic reagents. However, the reactions of the individual classes of compounds are not as straightforward as the addition reactions of organometallic compounds with aldehydes and ketones. Addition of a carbanion to the acyl carbon atom generates a tetrahedral intermediate that can decompose to give a ketone that will react further with another equivalent of the carbanion. 

Thus far, we have looked mainly at the reactions of oxygen, sulfur, and nitrogen nucleophiles with carbonyl compounds. All of these (and cyanide) have at least the potential to be leaving groups, once they are protonated. However, if we add carbanionic or hydridic nucleophiles to the carbonyl group, there are no circumstances in which these can behave as leaving groups. So additions of this type of nucleophile are nonreversible. 

Numerous examples have been reported of the reaction of sulphonium ylides with a 3-unsaturated carbonyl compounds whereby the ylide carbanion attacks the /3-carbon and the sulphonium group is displaced to afford a cyclopropane. Gruetzmacher reported numerous examples, and Gosselck et ai. reported ordinary addition reactions with the unusual ylides (62) and (63). The trans-isomers result from most reactions." The reaction of (64) with methyl acrylate afforded mainly the expected cyclopropane... 

Methylsulfinyl carbanion (dimsyl ion) is prepared from 0.10 mole of sodium hydride in 50 ml of dimethyl sulfoxide under a nitrogen atmosphere as described in Chapter 10, Section III. The solution is diluted by the addition of 50 ml of dry THF and a small amount (1-10 mg) of triphenylmethane is added to act as an indicator. (The red color produced by triphenylmethyl carbanion is discharged when the dimsylsodium is consumed.) Acetylene (purified as described in Chapter 14, Section I) is introduced into the system with stirring through a gas inlet tube until the formation of sodium acetylide is complete, as indicated by disappearance of the red color. The gas inlet tube is replaced by a dropping funnel and a solution of 0.10 mole of the substrate in 20 ml of dry THF is added with stirring at room temperature over a period of about 1 hour. In the case of ethynylation of carbonyl compounds (given below), the solution is then cautiously treated with 6 g (0.11 mole) of ammonium chloride. The reaction mixture is then diluted with 500 ml of water, and the aqueous solution is extracted three times with 150-ml portions of ether. The ether solution is dried (sodium sulfate), the ether is removed (rotary evaporator), and the residue is fractionally distilled under reduced pressure to yield the ethynyl alcohol. 

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