Alkynides alkylation

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

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. 

Metal acetylides or alkynides react with primary alkyl halides or tosylates to prepare alkynes (see Sections 5.5.2 and 5.5.3). 

They react with alkyl halides to give internal alkynes (see Section 5.5.2) via nucleophilic substitution reactions. This type of reaction also is known as alkylation. Any terminal alkyne can be converted to acetylide and alkynide, and then alkylated by the reaction with alkyl halide to produce an internal alkyne. In these reactions, the triple bonds are available for electrophilic additions to a number of other functional groups. 

We have already learnt that alkyl halides react with alcohols and metal hydroxide (NaOH or KOH) to give ethers and alcohols, respectively. Depending on the alkyl halides and the reaction conditions, both S l and Sn2 reactions can occur. Alkyl halides undergo a variety of transformation through Sn2 reactions with a wide range of nucleophiles (alkoxides, cyanides, acetylides, alkynides, amides and carboxylates) to produce other functional groups. 

Preparation of alkynes The reaction of primary alkyl halides and metal acetylides or alkynides (R C=CNa or R C=CMgX) yields alkynes. The reaction is limited to 1° alkyl halides. Higher alkyl halides tend to react via elimination. 

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

Silver nitrate test The compound to be tested is treated with a few drops of 1% alcoholic silver nitrate. A white precipitate indicates a positive reaction. This could be due to either silver chloride (reaction with a reactive alkyl halide), silver alkynide (reaction with a terminal alkyne), or the silver salt of a carboxylic acid (reaction with a carboxylic acid). 

Once the alkynide is formed, it can be treated with an alkyl halide to form more complex alkynes. This reaction is called an alkylation and is an example of nucleophilic substitution. 

This reaction works best with primary alkyl halides. When secondary or tertiary alkyl halides are used, the alkynide reacts like a base and this results in elimination of hydrogen halide from the alkyl halide to produce an alkene ... 

The insertion tendency decreases in the order r-BuLi > 5-BuLi > n-BuLi > PhLi > MeLi. These insertions can be carried out by using lithium alkanides, alkenides, alkynides, and aromatic or heterocyclic lithium compounds. The lithiation should not be carried out by using alkyl halides, because the lithium tellnrolates that are formed in the reaction may react with the alkyl halide reagent to produce organyl alkyl tellurides. ... 

One of the characteristic features of this approach is the successful fert-alkyl-al-kynyl coupling with dialkylaluminum alkynides which enables the introduction of a quaternary carbon in a position adjacent to an alkynyl group. Such transformation was previously achieved by the cross-coupling of ferf-alkyl chlorides with trialkynyl-aluminums as already described in this section [92]. The reaction of 98 with dimethyl-aluminum phenylacetylide (1.5 equiv.), readily prepared from lithium phenylacetylide and Me2AlCl, in toluene at -78 °C for 30 min resulted in formation of a cross-coupling product in 70 % yield. This result indicates the efficient and selective transfer of the alkynyl group from the aluminum center in dialkylaluminum alkynides as depicted in Sch. 65. 

In addition, conjugate addition of lithium alkynides and thermally unstable lithium carbenoids, which is very difficult to achieve in organocopper chemistry, is realized with this amphiphilic conjugate alkylation system (Sch. 98). 

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. 

The alkynide ion can undergo alkylation with a variety of alkylating reagents, such as haloalkanes and alkyl sulfates, with the formation of a carbon-carbon bond. The alkynide ion is also strongly basic so that elimination reactions may accompany or subvert the substitution reaction. Group I metal alkynides in liquid ammonia give mainly substitution products with primary haloalkanes but secondary and tertiary haloalkanes give mainly elimination products, as do 2-substituted primary haloalkanes (equation 1). 

Lithium alkynides in tetrahydrofuran or dioxane often give substitution products with secondary haloalkanes, while alkynide Grignard reagents do not usually react with haloalkanes except in the presence of other metals such as cobalt and copper. Substitution of iodine or bromine for chlorine in the halo-alkane often leads to an increased yield of the alkylation product and alkanesulfonates may give greater yields than haloalkanes. Scheme 1 illustrates examples of alkylation of haloalkanes and alkyl sulfates with alkynides of Group I metals. 

Lithium alkynylcuprates react with haloallenes to give similar skipped diacetylenes (see below). The related skipped enynes can be prepared by treatment of (pentadienyl)iron(tricarbonyl) halide complexes with dilithium trialkynylcuprates, the compounds being isolated as the iron(tricarbonyl)(diene) complexes (Scheme 4). Further examples of alkylation reactions of copper alkynides are illustrated in Scheme 5. Reaction between a lithium cyanoaikynecuprate and an iodoallene leads to a skipped diacetylene. This useful reaction has been used by Corey in his synthesis of hybridalactone (Scheme 6). °... 

As was previously remarked, water and its associated base are, respectively, too acidic and insufficiently basic to act as solvent and base for the preparation of alkynide ions. Lissel has shown, however, that with the addition of the crown ether 18-crown-6, alkylation of phenylacetylenes can occur with KOH and an iodoalkane (Scheme 29). 

Butadiyne has also been alkylated through the lithium alkynide. Thus, Holmes and Jones treated bis(trimethylsilyl)buta-l,3-diyne with MeLi in the presence of lithium bromide and obtained the monolithium alkynide, which was then alkylated in HMPA (Scheme 30). If the lithium alkynide was complexed with ethylenediamine then DMSO could be used as solvent. In addition, Himbert and Feustel prepared the lithium derivative of l-A A(-dialkylbuta-l,3-diyne by treatment of 4- -dialkyl-l,l,2-trichlorobut-l-en-3-yne with butyllithium. The lithium salt was not isolated but was alkylated to the l-alkyl-4-lV-di-alkylbuta-l,3-diyne (Scheme 31). 

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... 

Brefeldin (20) is a 13-membered lactone isolated from a number of sources and has a wide spectrum of biological activity. Many of the syntheses of this lactone use alkynes as intermediates. Thus, Living-house and Stevens used an elegant ring opening of a bicyclo[3.1.0]hexane to give the desired trans stereochemistry (Scheme 38), whereas in the synthesis of Kitahara and coworkers, a more conventional alkynide alkylation was involved (Scheme 39). 

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