Addition to carbon-heteroatom multiple bonds

L. Miginiac, Nucleophilic Addition to Carbon-Heteroatom Multiple Bonds O, S, N, P, in Handbook of Grignard Reagents (G. S. Silverman, P. E. Rakita, Eds.), Marcel Dekker Inc., New York, 1996, 361-372. 

Meerwein type arylations involving radical additions to carbon-heteroatom multiple bonds such as in isothiocyanates have been further extended to tandem reactions leading to heterocycles [117, 118]. 

Reactivity factors in additions to carbon-heteroatom multiple bonds are similar to those for the tetrahedral mechanism of nucleophilic substitution. If A and/or B are electron-donating groups, rates are decreased. Electron-attracting substituents increase rates. This means that aldehydes are more reactive than ketones. Aryl groups are somewhat deactivating compared to alkyl, because of resonance that stabilizes the substrate molecule, but is lost on going to the intermediate ... 

Nucleophilic Addition to Carbon-Heteroatom Multiple Bonds O, S, N, P... 

NUCLEOPHILIC ADDITION TO CARBON-HETEROATOM MULTIPLE BONDS... 

Addition to Carbon-Heteroatom Multiple Bonds. The behavior of r-BuLi in reactions with carbon-heteroatom r-bonds is relatively unremarkable and parallels that of other organolithium reagents. Even in cases where steric hindrance might be expected to lead to difficulties, product yields are reasonable. Thus, for example, tri-f-butylcarbinol (3-r-butyl-2,2,4,4-tetramethyl-3-pentanol) may be prepared by addition of r-BuLi to di-r-butyl ketone (2,2,4,4-tetramethyl-3-pentanone), although there is a significant amount of reduction in this case, and V-lithio-di-r-butylimines may be generated by addition of r-BuLi to r-butyl cyanide. ... 

In this chapter, we will be studying addition reactions to carbon-carbon multiple bonds this is the converse process of the eliminations that we studied in the previous chapter. Addition to carbon-heteroatom multiple bonds is coming up in Chapter 14. Nucleophiles, electrophiles, and radicals can all add across double bonds first, we will concentrate on electrophiles and radicals, as nucleophiles only add readily when the double bond bears a group (such as a carbonyl, nitro, or nitrile Chapter 17) capable of accepting electron density. Reactions with electrophiles or radicals add two moieties, atoms or groups, by a stepwise process the two atoms or groups are not added simultaneously. However, there is another class of reactions where the two new bonds are made simultaneously—these are called concerted reactions. 

One must be well aware of the characteristic features concerning the addition of organometallic reagents to carbon-heteroatom multiple bonds such as the carbon-oxygen and the carbon-nitrogen double bonds in order to develop a catalytic asymmetric process for this type of reaction. 

In contrast to the related organoboranes, which are mostly used in the addition to non-polar carbon-carbon multiple bonds, aluminum hydrides have found their widest use in organic synthesis in the addition reaction to polar carbon-carbon and carbon-heteroatom multiple bonds including carbonyl, nitrile and imino groups as well as their a,(J-unsaturated analogs. Although these reduction reactions are also sometimes referred as hydroalumination reactions in the Hterature, they are outside the scope of this review. 

Addition of radicals to carbon-carbon or carbon-heteroatom multiple bonds followed by the trapping of resulting radicals with a hydrogen atom source... 

In addition to olefins, carbon heteroatom multiple bonds can also participate in the cycloaddition with various carbonyl ylides (Scheme 4.28). 

Addition reactions to other carbon-heteroatom MULTIPLE BONDS (see also Grignard reaction, Hydrolysis, Reduction reactions)... 

Addition reactions of carbon radicals to C—O and C—N multiple bonds are much less-favored than additions to C—C bonds because of the higher ir-bond strengths of the carbon-heteroatom multiple bonds. This reduction in exothermicity (additions to carbonyls can even be endothermic) often reduces the rate below the useful level for bimolecular additions. Thus, acetonitrile and acetone are useful solvents because they are not subject to rapid radical additions. However, entropically favored cyclizations to C—N and C—O bonds are very useful, as are fragmentations (see Chapter 4.2, this volume). 

The electrophile shown in step 2 is the proton. In almost aU the reactions considered in this chapter, the electrophihc atom is either hydrogen or carbon. Note that step 1 is exactly the same as step 1 of the tetrahedral mechanism of nucleophilic substim-tion at a carbonyl carbon (p. 1255), but carbon groups (A, B = H, alkyl aryl, etc.) are poor leaving groups so that substitution does not compete with addition. For carboxylic acids and their derivatives (B = OH, OR, NH2, etc.) much better leaving groups are available and acyl substitution predominates (p. 1254). It is thus the nature of A and B that determines whether a nucleophilic attack at a carbon-heteroatom multiple bond will lead to substitution or addition. 

Double bonds in conjugation with the carbon-heteroatom multiple bond also lower addition rates, for similar reasons but, more important, may provide competition from 1,4-addition (p. 1008). Steric factors are also quite important and contribute to the decreased reactivity of ketones compared with aldehydes. Highly hindered ketones like hexamethylacetone and dineopentyl ketone either do not undergo many of these reactions or require extreme conditions. 

This is a reaction with high atom economy and without the use of organometallic reagents, additives, or redox systems. Such an acetoxypalladation-initiated carbon-heteroatom multiple bond insertion-protonolysis system may extend the scope of transition metal-catalysed reactions pertaining to the insertion of carbon-heteroatom multiple bonds into metal-carbon bonds, and provide a new methodology in organic synthesis. The generality of the present catalytic system is shown in Table 10.2.[3]... 

Owing to its tendency to undergo nucleophilic addition with carbonyl groups and other electrophilic carbon-heteroatom multiple bonds (C=NR, C=N, C=S), n-BuLi is usually not the reagent of choice for the generation of enolate anions or enolate equivalents from active hydrogen conpounds. This is done most conveniently using the less nucleophilic lithium dialkylamides (e.g. Lithium DUsopropylamide (LDA), Lithium 2,2,6,6-Tetra-... 

Nucleophilic additions to alkenes and alkynes are also possible, but these reactions generally require that the substrate have substituents that can stabilize a carbanionic intermediate. Therefore, nucleophilic additions are most likely for compoimds with carbon-heteroatom multiple bonds, such as carbonyl compounds, imines, and cyano compounds. We may distinguish two main types of substituents that activate alkenes and alkynes for nucleophilic attack. The first type consists of those activating groups (labeled AG in equation 9.79) that can stabilize an adjacent carbanion by induction. ... 

Regiochemistry is ordinarily not a concern in the addition of nucleophiles to structures having carbon-heteroatom multiple bonds that are not conjugated with carbon-carbon double or triple bonds, because only 1,2-addition is expected. If the addition creates a new chiral center, however, then stereoisomeric addition products can be formed. Considerable interest in this area was sparked by a report by Cram that nucleophilic addition to ketones having chiral a carbon atoms gave unequal yields of the possible diastereomeric adducts. For example, addition of ethyllithium to the methyl ketone (+ )-92 gave primarily the erythro product (+ )-93. 

Hydrocyanation is the addition of HCN across carbon-carbon or carbon-heteroatom multiple bonds to form products containing a new C-C bond. The majority of examples from organometallic chemistry involve the addition of HCN across carbon-carbon multiple bonds, as shown in Equations 16.2 and 16.3. Lewis acids and peptides have been used to catalyze the enantioselective addition of HCN to aldehydes and imines to form cyanohydrins and precursors to amino acids.The addition of HCN to unactivated olefins requires a catalyst because HCN is not sufficiently acidic to add directly to an olefin, and the C-H bond is strong enough to make additions by radical pathways challenging. However, a large number of soluble transition metal compounds catalyze the addition of HCN to alkenes and alkynes. 

F. W. Stacey, J. F. Harris, Jr, Formation of Carbon-Heteroatom Bonds by Free Radical Chain Additions to Carbon-Carbon Multiple Bonds, Org. React. 1963,13, 150-376. 

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