Alkynide anions

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. 

The acetylenic hydrogen is weakly acidic (pKa 25) and can be removed with a strong base (e.g. NaNH2) to give an anion (called an alkynide anion or acetylide ion). 

An alkyne Sodium amide An alkynide anion R must be methyl or 1° and... 

The alkyl halide used with the alkynide anion must be methyl or primary and also unbranched at its second (beta) carbon. 

Preparation of the alkynide anion involves simple Bronsted-Lowry acid-base chemistry. 

The alkynide anion is a Lewis base and reacts with the alkyl halide (as an electron pair acceptor, a Lewis acid). 

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

The displaced group X often is a halide ion (chloride, bromide, or iodide), and if the entering nucleophile Nu e is an alkynide anion, the reaction leads to formation of a carbon-carbon bond ... 

However, the synthesis as written would fail because the alkyne is a weaker acid than the alcohol (Section 11-8), and the alkynide anion would react much more rapidly with the acidic proton of the alcohol than it would displace bromide ion from carbon ... 

The —CH2CH2OH unit can be appended to an alkynide anion by reaction with ethylene oxide. 

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

Several examples of alkynic ketone formation have been recorded since Weinreb s first examples. A Diels-Alder strategy for Ae synthesis of mevinolin required the preparation of alkynic ketone (24). Standard methods, calling for the addition of the alkynide anion to an aldehyde followed by oxidation, lead to extensive degradation and by-product formation. The Weinreb methodology was clearly more effective (Scheme 8). ... 

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. ... 

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 acetylenic proton of ethyne or any terminal alkyne (pA 25) can be removed with a strong base such as sodium amide (NaNH2). The result is an alkynide anion. 

Alkynide anions are useful nucleophiles for carbon-carbon bond forming reactions with primary alkyl halides or other primary substrates. 

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

The alkynide anion acts as a nucleophile and displaces the halide ion from the primary alkyl halide. We now recognize this as an 5 2 reaction (Section 6.5). 

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

Use of a secondary or tertiary substrate causes E2 elimination instead of substitution because the alkynide anion is a strong base as well as a good nucleophile. 

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. 

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 ... 

The alkynide anion and alkyl halide have complementary polarities. 

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. 

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. 

If we have a terminal alkyne, such as could be made from an appropriate vicinal dihalide, we can use the alkynide anion derived from it to form carbon—carbon bonds by nucleophilic substitution. 

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