Acetylide nucleophiles

For die lactone target L shown below, cleavage of the lactone ring gives a Y -hydroxy acid. This can be disconnected at any one of the three intervening bonds between the hydroxyl group and the carbonyl group (a, b, c). 

While the carbonyl group is a very common starting point for bond disconnections in retrosynthetic analysis, an olefinic or acetylenic unit is also a useful reference point in many instances. This is because a terminal acetylene can be used as an 

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A wide array of substances can be prepared using nucleophilic substitution reactions. In fact, we ve already seen examples in previous chapters. The reaction of an acetylide anion with an alkyl halide (Section 8.8), for instance, is an Sn2 reaction in which the acetylide nucleophile replaces halide. 

In addition, the same group found that reaction of [2,1-c] IFs 165 and 166 with an acetylide nucleophile gave diols 167a,b subsequent treatment with SOCI2 induced a cascade cyclization forming [l,2-a]IF dimers 168a,b in low yield (Scheme 46)... 

Cyanide and Acetylide Nucleophiles (Making a Carbon-Carbon Bond)... 

At first, this transformation might seem challenging, since no reaction exists that adds an alkynyl group to an alkene. However, a systematic approach to these problems always begins with the ending a retrosynthesis of the desired product. Once the alkyne TM is disconnected to give an acetylide nucleophile and a five-carbon electrophile (1-bromopentane), the solution becomes clear. 

As we have already seen, an acetylide anion is a strong base. An acetylide anion is also a nucleophile it has an unshared pair of electrons that it can donate to another atom to form a new covalent bond. In this instance, an acetylide anion donates its unshared pair of electrons to the carbon of a methyl or primary haloalkane, and in so doing, the acetylide nucleophile replaces the halogen atom. This type of reaction is called a nucleophilic substitution. For example, treating sodium acetylide with 1-bromobutane gives 1-hexyne. 

Now, let s draw out the forward scheme. Acetylene is reduced to ethylene using H2 and Lindlar s catalyst. HBr addition, followed by Sn2 substitution with an acetylide nucleophile (made by deprotonation of acetylene with sodium amide) gives 1-butyne. Reduction to 1-butene with H2 and Lindlar s catalyst followed by anrt-Markovnikov addition of HBr in the presence of peroxide produces 1-bromobutane. A substitution reaction with sodium acetylide gives 1-... 

Cumulenic anions, C=C=C and C=C=C=C, without strongly electron-withdrawing substituents are much stronger bases than acetylides, "CsC- and are therefore also stronger nucleophiles. In view of the poor stability of the cumulenic anions at normal temperatures this is a fortunate circumstance the usual functionalization reactions such as alkylation, trimethylsilylation and carboxylation in most cases proceed at a sufficient rate at low temperatures, provided that the... 

The only common synthons for alkynes are acetylide anions, which react as good nucleophiles with alkyl bromides (D.E. Ames, 1968) or carbonyl compounds (p. 52, 62f.). 

Next an alkyl halide (the alkylating agent) is added to the solution of sodium acetylide Acetylide ion acts as a nucleophile displacing halide from carbon and forming a new carbon-carbon bond Substitution occurs by an 8 2 mechanism... 

The properties of organometallic compounds are much different from those of the other classes we have studied to this point Most important many organometallic com pounds are powerful sources of nucleophilic carbon something that makes them espe cially valuable to the synthetic organic chemist For example the preparation of alkynes by the reaction of sodium acetylide with alkyl halides (Section 9 6) depends on the presence of a negatively charged nucleophilic carbon m acetylide ion... 

These compounds are sources of the nucleophilic anion RC=C and their reaction with primary alkyl halides provides an effective synthesis of alkynes (Section 9 6) The nucleophilicity of acetylide anions is also evident m their reactions with aldehydes and ketones which are entirely analogous to those of Grignard and organolithium reagents... 

Conjugate addition is most often observed when the nucleophile (Y ) is weakly basic The nucleophiles m the two examples that follow are C=N and C6H5CH2S respectively Both are much weaker bases than acetylide ion which was the nucleophile used m the example illustrating direct addition... 

Alkynes of the type RC=CH may be prepared by nucleophilic substitution reactions in which one of the starting materials is sodium acetylide (Na C=CH). 

You have already had considerable experience with caibanionic compounds and their- applications in synthetic organic chemistry. The first was acetylide ion in Chapter 9, followed in Chapter 14 by organometallic compounds—Grignaid reagents, for exanple—that act as sources of negatively polarized car bon. In Chapter 18 you learned that enolate ions—reactive intermediates generated from aldehydes and ketones—are nucleophilic, and that this property can be used to advantage as a method for carbon-carbon bond formation. 

Acetylenes are sufficiently acidic to react with sodium metal to generate acetylides, useful nucleophiles in the formation of carbon-carbon bonds. The reaction is classically carried out in liquid ammonia, which is a good solvent for alkali metals but which is troublesome to handle. Two convenient modifications of the acetylide generation reaction overcome this difficulty and are discussed below along with the classical method. 

The presence of a negative charge and an unshared electron pair on carbon makes acetylide anions strongly nucleophilic. As a result, they react with many different kinds of electrophiles. 

We won t study the details of this substitution reaction until Chapter 11 but for now can picture it as happening by the pathway shown in Figure 8.6. The nucleophilic acetylide ion uses an electron pair to form a bond to the positively polarized, electrophilic carbon atom of bromomethane. As the new C-C bond forms, Br- departs, taking with it the electron pair from the former C-Br bond and yielding propyne as product. We call such a reaction an alkylation because a new alkyl group has become attached to the starting alkyne. 

The nucleophilic acetylide anion uses its electron lone pair to form a bond to the positively polarized, electrophilic carbon atom of bromomethane. As the new C-C bond begins to form, the C-Br bond begins to break in the transition state. 

Retrosynthetic cleavage of the indicated bond in 9 provides acetylenic aldehyde 23 as a potential precursor. It was anticipated that the action of a suitable base on 23 would result in the formation of an acetylide anion, a competent carbon nucleophile that could... 

The monolithium salt of 4-hydroxy-4-(phenylethynyl)-2.5-cyclohexadienone (12), prepared in situ by the addition of lithium acetylide to /7-benzoquinone, was treated with methylmagnesium chloride in l HF-TMEDA or in THF —DMPU. The syn-, 4-addition adduct 13, derived from intramolecular delivery of the carbon nucleophile by the hydroxy oxygen, as well as the <7s-1,4-diol 14, obtained via intermolecular 1,2-addition, were obtained in varying amounts depending on the conditions. The selectivity on 1,4- to 1,2-addition increased by the addition of cation chelating agents such as DMPU, TMEDA, and 15-crown-5. Although the 1,4 to 1,2... 

Potassium or lithium derivatives of ethyl acetate, dimethyl acetamide, acetonitrile, acetophenone, pinacolone and (trimethylsilyl)acetylene are known to undergo conjugate addition to 3-(t-butyldimethylsiloxy)-1 -cyclohexenyl t-butyl sulfone 328. The resulting a-sulfonyl carbanions 329 can be trapped stereospecifically by electrophiles such as water and methyl iodide417. When the nucleophile was an sp3-hybridized primary anion (Nu = CH2Y), the resulting product was mainly 330, while in the reaction with (trimethylsilyl)acetylide anion the main product was 331. 

Other carbanionic groups, such as acetylide ions, and ions derived from a-methylpyridines have also been used as nucleophiles. A particularly useful nucleophile is the methylsulfinyl carbanion (CH3SOCHJ), the conjugate base of DMSO, since the P-keto sulfoxide produced can easily be reduced to a methyl ketone (p. 549). The methylsulfonyl carbanion (CH3SO2CH2 ), the conjugate base of dimethyl sulfone, behaves similarly, and the product can be similarly reduced. Certain carboxylic esters, acyl halides, and DMF acylate 1,3-dithianes (see 10-10. )2008 Qxj(jatjye hydrolysis with NBS or NCS, a-keto aldehydes or a-... 

We see from these examples that many of the carbon nucleophiles we encountered in Chapter 10 are also nucleophiles toward aldehydes and ketones (cf. Reactions 10-104-10-108 and 10-110). As we saw in Chapter 10, the initial products in many of these cases can be converted by relatively simple procedures (hydrolysis, reduction, decarboxylation, etc.) to various other products. In the reaction with terminal acetylenes, sodium acetylides are the most common reagents (when they are used, the reaction is often called the Nef reaction), but lithium, magnesium, and other metallic acetylides have also been used. A particularly convenient reagent is lithium acetylide-ethylenediamine complex, a stable, free-flowing powder that is commercially available. Alternatively, the substrate may be treated with the alkyne itself in the presence of a base, so that the acetylide is generated in situ. This procedure is called the Favorskii reaction, not to be confused with the Favorskii rearrangement (18-7). ... 

The reaction proceeds with isolated double bonds and electron-rich alkynes. Electron-withdrawing groups in the acetylene moiety decelerated the reaction. A plausible mechanism implies the activation of the olefin by coordination of the metal triflate followed by nucleophilic attack of the acetylene or acetylide (Scheme 31). 

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