Alkylation of alkynide anions

The alkylation of j p-carbon can, in principle, involve the alkyne (acetylene) either as the nucleophile or the electrophile. In practice by far the most important process involves the alkyne as nucleophile since the acidity of the alkyne proton (pK = 25) allows the ready formation of alkynide ions. These are excellent nucleophiles and they readily undergo acylation and alkylation with appropriate electrophiles. The recent introduction of palladium-catalyzed reactions, usually involving copper(I) salts but also other cations, has greatly increased the use made of arylation and vinylation reactions. In this chapter only the alkylation of the alkynide ion will be discussed acylation, vinylation and arylation reactions are discussed elsewhere. The alkylation of alkynide anions is a reaction of considerable synthetic use and has been extensively reviewed. ... 

Primary alkyl halides should be used in the alkylation of alkynide anions, so as to avoid competition by elimination. 

A General Principles of Structure and Reactivity Illustrated by the Alkylation of Alkynide Anions... 

The alkylation of alkynide anions illustrates several essential aspects of structure and reactivity that have been important to our study of organic chemistry thus far. 

You have learned quite a few tools that are useful for organic synthesis, including nucleophilic substitution reactions, elimination reactions, and the hydrogenation reactions covered in Sections 7.12—7.14. Now we wiU consider the logic of organic synthesis and the important process of retrosynthetic analysis. Then we will apply nucleophilic substitution (in the specific case of alkylation of alkynide anions) and hydrogenation reactions to the synthesis of some simple target molecules. 

In this chapter we described methods for the synthesis of alkenes using dehydrohalogenation, dehydration of alcohols, and reduction of alkynes. We also introduced the alkylation of alkynide anions as a method for forming new carbon-carbon bonds, and we introduced retrosynthetic analysis as a means of logically planning an organic synthesis. 

Alkylation of alkynide anions RCECr + R —X- RCECR (Section 7.11)... 

In some respects, the alkylation of enolate anions resembles nucleophilic substitution. We recall that many nucleophiles displace leaving groups from primary alkyl halides by an Sj 2 mechanism (Section 9.3). A similar reaction occurs with secondary alkyl halides, but competing elimination reactions also occur. Primary alkyl halides react with carbanions, such as the alkynide ion, by an Sj 2 mechanism. (Secondary alkyl halides react not only in displacement reactions but also in elimination reactions because the alkynide ion is a strong base.)... 

R,8S)-(+)-Disparlure (12) is the female sex pheromone of the gypsy moth (Lymantria dispar). Advent of Sharpless asymmetric dihydroxylation (AD) allowed several new syntheses of 12 possible. Sharpless synthesized 12 as shown in Scheme 17 [27]. Scheme 18 summarizes Ko s synthesis of 12 employing AD-mix-a [28]. He extended the carbon chain of A by Payne rearrangement followed by alkylation of an alkynide anion with the resulting epoxide to give B. Keinan developed another AD-based synthesis of 12 as shown in Scheme 19 [29]. Mit-sunobu inversion of A to give B was the key step, and the diol C could be purified by recrystallization. 

Electrostatic potential maps illustrate the complementary nucleophilic and electrophilic character of the alkynide anion and the alkyl halide. 

The alkynide anion is derived from 1-butyne by alkylation of acetylene. This analysis suggests the following synthetic sequence ... 

The low acidity of 1-alkynes means that strong bases must be used to form the alkynide ions and that water is not a suitable solvent aqueous solutions have a very low concentration of alkynide ions. Some transition metal alkynides can be prepared by precipitation from aqueous solution because their solubilities are very low. Suitable solvents for the preparation of alkynide ions must be less acidic than the alkyne, and preferably allow the alkyne and the alkynide ion to remain in solution. Liquid ammonia, te-trahydrofuran, ether and hydrocarbons have all been used, particularly the first, the alkynide anion being readily formed by metal amides. Alkynides of many types have been prepared from various metals. Besides Groups I and III, copper(I), silver, gold(I), zinc, mercury and, more recently, aluminum alkynides have been synthesized. The alkynides of Groups I and II have been principally used as nucleophiles in alkylation reactions, but there are now many examples of other metal alkynides in this role. Palladium-catalyzed reactions, as remarked above, have become increasingly important for the reactions of alkynides of metals other than Groups I and II, but these have not usually involved alkylation. 

This process is much less common than nucleophilic substitution by alkynide anions and the actual mechanisms of the reactions in which electrophilic substitution of an sp-carbon appears to occur probably do not involve simple substitution. Kende and coworkers, for example, have reacted tertiary enol-ate anions with chloroalkynes and obtained the corresponding alkylated products (Scheme 32). These... 

The following are general and specific examples of carbon—carbon bond formation by alkylation of an alkynide anion with a primary alkyl halide. 

One very important aspect of retrosynthetic analysis is being able to identify those atoms in a target molecule that could have had complementary (opposite) charges in synthetic precursors. Consider, for example, the synthesis of 1-cyclohexyl-1-butyne. On the basis of reactions learned in this chapter, you might envision an alkynide anion and an alkyl halide as precursors having complementary polarities that when allowed to react together would lead to this molecule ... 

Continuing to work backward one hypothetical reaction at a time, we realize that a synthetic precursor of 1 -butene is 1 -butyne. Addition of 1 mol of hydrogen to 1 -butyne would lead to 1-butene. With 1-butyne as our new target, and bearing in mind that we are told that we have to construct the carbon skeleton from compounds with two carbons or fewer, we realize that 1 -butyne can be formed in one step from ethyl bromide and acetylene by an alkynide anion alkylation. 

Figure 7.8 The reaction of ethynide (acetylide) anion and chloromethane. Electrostatic potential maps illustrate the complementary nucleophilic and electrophilic character of the alkynide anion and the alkyl halide. The dipole moment of chloromethane is shown by the red arrow.

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