Addition of Carbon Nucleophiles to Carbonyl Groups

The addition of carbon nucleophiles, including organometallic compounds, enolates, and enols, to carbonyl groups is one of the main methods of formation of carbon-carbon bonds. Such reactions are extremely important in synthesis and will be discussed extensively in Part B. Here, we will examine some of the fundamental mechanistic aspects of addition of carbon nucleophiles to carbonyl groups. 

Organolithium and organomagnesium reagents are highly reactive toward most carbonyl compounds. With aldehydes and ketones, the tetrahedral adduct is stable, and alcohols are isolated after hydrolysis of the product alkoxide salt. 

In the case of esters, carboxylate anions, amides, and acid chlorides, the tetrahedral adduct may undergo elimination. The elimination forms a ketone, permitting a subsequent addition to occur. The rate at which breakdown of the tetrahedral adduct 

Im most cases, the product ratio can be controlled by choice of reaction conditions. Ketones are isolated under conditions where the tetrahedral intermediate is stable until hydrolyzed, whereas alcohols are formed when the tetrahedral intermediate decomposes in the presence of unreacted organometallic reagent. Examples of synthetic application of this class of reactions will be discussed in Section 7.2 of Part B. 

The rate laws for the reaction of several aromatic ketones with alkyllithium reagents has been examined. The reaction of 2,4-dimethyl-4 -methylthiobenzo-phenone with methyllithium in ether exhibits the rate law 

The addition of carbon nucleophiles, including organometallic compoimds, enolates, or enols, and ylides to carbonyl groups is an important method of formation of carbon- 

SECTION 8.3. ADDITION OF CARBON NUCLEOPHILES TO CARBONYL GROUPS 

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Stereoselective formation of C-C bonds in nature is assisted by enzymes named lyases, which catalyze usually reversible addition of carbon nucleophiles to carbonyl group. Aldolases belong to the group of lyases. They occur in all organisms being involved in the metabolism of carbohydrates as well as amino- and hydroxy acids. Over 30 aldolases have been identified to date. 

The reactions that are discussed in this section involve addition of carbon nucleophiles to carbonyl centers having a potential leaving group. The tetrahedral intermediate formed in the addition step reacts by expulsion of the leaving group. The overall... 

The most general methods for the syntheses of 1,2-difunctional molecules are based on the oxidation of carbon-carbon multiple bonds (p. 117) and the opening of oxiranes by hetero atoms (p. 123fl.). There exist, however, also a few useful reactions in which an a - and a d -synthon or two r -synthons are combined. The classical polar reaction is the addition of cyanide anion to carbonyl groups, which leads to a-hydroxynitriles (cyanohydrins). It is used, for example, in Strecker s synthesis of amino acids and in the homologization of monosaccharides. The ff-hydroxy group of a nitrile can be easily substituted by various nucleophiles, the nitrile can be solvolyzed or reduced. Therefore a large variety of terminal difunctional molecules with one additional carbon atom can be made. Equally versatile are a-methylsulfinyl ketones (H.G. Hauthal, 1971 T. Durst, 1979 O. DeLucchi, 1991), which are available from acid chlorides or esters and the dimsyl anion. Carbanions of these compounds can also be used for the synthesis of 1,4-dicarbonyl compounds (p. 65f.). 

Formation of C-C bonds remains the ultimate challenge to the synthetic chemist. The employment of new synthetic methods in complex target synthesis can be frustrated by a lack of functional group tolerance and substrate specificity. These problems can be somewhat alleviated within conjugate addition reactions by the use of secondary amine catalysts where a number of important and highly selective methods have been developed. Two principle classes of nucleophile have been shown to be effective in the iminium ion activated conjugate addition of carbon nucleophiles to a,P-unsaturated carbonyl systems aryl, heteroaromatic and vinyl... 

We will now turn our attention to the addition of carbon nucleophiles to the carbonyl group. This type of reaction represents a very important group of reactions that have wide synthetic utility, because they allow for the extension of the carbon backbone of the starting material. 

Dioxobenzocyclobutene has also attracted interest for organic synthesis. In particular, much attention has been paid to the addition of carbon nucleophiles to the carbonyl group for transformation to naphthoquinone or indanone derivatives. Double additions of excess vinyllithium to (1,2-dioxobenzocyclo-butene)chromium complex 52 at -78 °C gave the tricarbonylchromium complex of 5,10-dioxobenzocyclooctene 53 in 87% yield without formation of simple diadduct (Eq. 38) [37]. Obviously, the product 53 was formed by a double addition of vinyllithium and subsequent anionic oxy-Cope rearrangement. 

As noted previously, conjugate addition of a nucleophile to the j3 carbon of an cr,/3-unsaturated aldehyde or ketone leads to an enolate ion intermediate, which is protonated on the a carbon to give the saturated product (Figure 19.16). The net effect is addition of the nucleophile to the C=C bond, with the carbonyl group itself unchanged. In fact, of course, the carbonyl group is crucial to the success of the reaction. The C=C bond would not be activated for addition, and no reaction would occur, without the carbonyl group. 

The addition of a nucleophile to a polar C=0 bond is the key step in thre< of the four major carbonyl-group reactions. We saw in Chapter 19 that when. nucleophile adds to an aldehyde or ketone, the initially formed tetrahedra intermediate either can be protonated to yield an alcohol or can eliminate th< carbonyl oxygen, leading to a new C=Nu bond. When a nucleophile adds to carboxylic acid derivative, however, a different reaction course is followed. Tin initially formed tetrahedral intermediate eliminates one of the two substituent originally bonded to the carbonyl carbon, leading to a net nucleophilic acy substitution reaction (Figure 21.1. ... 

Azirines (three-membered cyclic imines) are related to aziridines by a single redox step, and these reagents can therefore function as precursors to aziridines by way of addition reactions. The addition of carbon nucleophiles has been known for some time [52], but has recently undergone a renaissance, attracting the interest of several research groups. The cyclization of 2-(0-tosyl)oximino carbonyl compounds - the Neber reaction [53] - is the oldest known azirine synthesis, and asymmetric variants have been reported. Zwanenburg et ah, for example, prepared nonracemic chiral azirines from oximes of 3-ketoesters, using cinchona alkaloids as catalysts (Scheme 4.37) [54]. 

When a carbonyl group is bonded to a substituent group that can potentially depart as a Lewis base, addition of a nucleophile to the carbonyl carbon leads to elimination and the regeneration of a carbon-oxygen double bond. Esters undergo hydrolysis with alkali hydroxides to form alkali metal salts of carboxylic acids and alcohols. Amides undergo hydrolysis with mineral acids to form carboxylic acids and amine salts. Carbamates undergo alkaline hydrolysis to form amines, carbon dioxide, and alcohols. 

The previous sections dealt with reactions in which the new carbon-carbon bond is formed by addition of the nucleophile to a carbonyl group. Another important method for alkylation of carbon nucleophiles involves addition to an electrophilic multiple bond. The electrophilic reaction partner is typically an a,(3-unsaturated ketone, aldehyde, or ester, but other electron-withdrawing substituents such as nitro, cyano, or sulfonyl also activate carbon-carbon double and triple bonds to nucleophilic attack. The reaction is called conjugate addition or the Michael reaction. 

Asymmetric addition of small-molecule nucleophiles to carbonyl groups and their derivatives are catalyzed by either Lewis acids or Lewis bases. Carbon dioxide is now a promising building block for as5mimetric organic synthesis. 

Fig. 32 Energy diagram that illustrates the major configurations, reactant [54], product [55] and carbanion [56], that contribute to the addition of a nucleophile to a carbonyl group (109). In the transition state region there is a build-up of negative charge on carbon due to the carbanion configuration [56]...

Carbonyl reactions may be understood in terms of two basic processes addition of a nucleophile to the carbonyl carbon (Equation 8.1) and removal of a proton from the carbon adjacent to the carbonyl group (Equation 8.2). In the first process the carbonyl molecule is acting as a Lewis acid, and in the second... 

When the carbonyl group bears as one substituent a group that can potentially depart as a Lewis base, the most common result of addition of a nucleophile to the carbonyl carbon is elimination to regenerate a carbon-oxygen double bond... 

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