Carbon-heteroatom multiple bonds, nucleophilic addition

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. 

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. 

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... 

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. 

NUCLEOPHILIC ADDITION TO CARBON-HETEROATOM MULTIPLE BONDS... 

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. 

Click chemistry is a chemical concept enunciated by Barry Sharpless, Scripps Research Institute, USA, in 2001, which highlights the importance of using a set of powerful, highly reliable, selective reactions under simple reaction conditions to join small molecular units together quickly for the rapid synthesis of new compounds via heteroatom links and create molecular diversity. Several types of reactions have been identified that fulfill the criteria- thermodynamically favored reactions that lead specifically to one product such as nucleophilic ring opening reactions of epoxides and aziridines, nonaldol type carbonyl reactions, additions to carbon-carbon multiple bonds, Michael additions, and cycloaddition reactions. The best-known cHck reactions are the copper-catalyzed reaction of azides and alkynes or the so-called CuAAC reaction and the thiol-ene reaction. 

Organometallics react with this sink by addition to the multiple bond (path Ad r). The more covalent, less reactive organometallics, like R2Cd, react very slowly with almost all of these sinks, whereas organomagnesiums, RMgX, and organolithiums react quickly. Complexation of the metal ion to the Y heteroatom catalyzes this reaction. Organometallics react much faster as nucleophiles with polarized multiple bonds than as bases with the adjacent C-H bonds, (carbon-acid, carbon-base proton transfer is slow). C=Y example ... 

An extension of Hashmi s Au(III)-catalyzed phenol synthesis [81] to furan substrates 9 bearing an additional alkyne moiety allowed the preparation of C6-C7-heterofused benzofuran 11 (Scheme 9.3) [82]. According to the proposed mechanism, the Au(III)-catalyzed arene formation reaction generates o-alkynylphenol 10. A subsequent Au(III)-catalyzed cycloisomerization of the latter, following the general mechanism for an intramolecular nucleophilic addition of heteroatom to transition metal-activated carbon-carbon multiple bonds, gives 11 (Scheme 9.3). 

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