Addition of Nucleophiles to Carbonyl Compounds

The benefits of pressure or Lewis acid catalysis for the addition of nucleophiles to carbonyl compounds is also well established, e.g. in various aldol processes or allylation reactions. The combination of the two methods, however, has rarely been applied. 

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TABLE 1.2. Equilibrium constants for addition of nucleophiles to carbonyl compounds. ... 

Alcohols can be obtained from many other classes of compounds such as alkyl halides, amines, al-kenes, epoxides and carbonyl compounds. The addition of nucleophiles to carbonyl compounds is a versatile and convenient methc for the the preparation of alcohols. Regioselective oxirane ring opening of epoxides by nucleophiles is another important route for the synthesis of alcohols. However, stereospe-cific oxirane ring formation is prerequisite to the use of epoxides in organic synthesis. The chemistry of epoxides has been extensively studied in this decade and the development of the diastereoselective oxidations of alkenic alcohols makes epoxy alcohols with definite configurations readily available. Recently developed asymmetric epoxidation of prochiral allylic alcohols allows the enantioselective synthesis of 2,3-epoxy alcohols. 

Carbinolamine (Section 19.8) A molecule that contains the R2C(OH)NH2 functional group. Carbinolamines are produced as intermediates during the nucleophilic addition of amines to carbonyl compounds. 

In Chaptare we discussed the role of base and ecid catalysts in the direct addition of alcohols to carbonyl compounds to form hemiacetals. The reasoning—that base makes nucleophiles more nucleophilic and acid makes carbonyl groups more electrophilic—is the same here. 

The cyclizations of 85 to 86 and of 87 to 88 represent the simple cases in which the internal nucleophile is the OH group of an alcohol [64,65]. An in situ generated hydroxy group, as in the addition of alcohols to carbonyl compounds, can also participate in phenylseleno-etherification reactions. This is examplified by the conversion of 89 into 90 in the presence of benzyl alcohol [66]. Another type of OH, which gives rise to these reactions is the enolic OH of /1-dicarbonyl compounds. Thus, Ley reported that compounds like 91 and 93 can be transformed into the cyclic derivatives 92 and 94 by treatment with N-PSP 11 in the presence of zinc iodide [67]. The cyclization of 95 to 96 represents a simple example of the selenolactonization process [68, 69]. It is interesting to note that the various cyclization reactions indicated in Scheme 14, which require different electrophilic selenenylating agents, can all be effected with phenyselenyl sulfate [70]. 

There are many examples of the stereoselective addition of nucleophiles to carbonyl groups in which chelation to the titanium center should be critical—reported examples include the stereoselective hydride reduction of a- or /3-hydroxyketones (Eq. 305) [684-686], of a-phosphino ketones [687], of a-sulfonylketones [688], and of an a,/3-unsaturated carbonyl compound in a 1,4-fashion [689]. The stereoselective addition of organometallic compounds such as Grignard [669,690], zinc [691,692], copper [693], and other reagents [11] to carbonyl and related compoimds Ijy taking advantage of titanium chelation is a well established method in the stereoselective... 

J. Fastrez, Estimation of the Free Energies of Addition of Nucleophiles to Conjugated Carbonyl Compounds and to Acyl Derivatives, J. Am. Chem. Soc. 1977, 99, 7004. 

A second important reaction type considered in this chapter is conjugate addition, which involves addition of nucleophiles to electrophilic double or triple bonds. A crucial requirement for this reaction is an electron-withdrawing group (EWG) that can stabilize the negative charge on the intermediate. We focus on reactions between enolates and a,(3-unsaturated carbonyl compounds and other electrophilic alkenes such as nitroalkenes. 

The most useful methods for the formation of C-C bonds are based on the addition of C-nucleophiles to carbonyl compounds. Among the many variations of this basic scheme phosphorus ylides, capable of olefinating aldehydes or ketones in a single step, have proven to be exceedingly valuable reagents in organic synthesis. 

Bismuth-Catalyzed Addition of Silyl Nucleophiles to Carbonyl Compounds and Imines... 

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