Substitution, nucleophilic alkyne anions

Terminal alkyne anions are popular reagents for the acyl anion synthons (RCHjCO"). If this nucleophile is added to aldehydes or ketones, the triple bond remains. This can be con verted to an alkynemercury(II) complex with mercuric salts and is hydrated with water or acids to form ketones (M.M.T. Khan, 1974). The more substituted carbon atom of the al-kynes is converted preferentially into a carbonyl group. Highly substituted a-hydroxyketones are available by this method (J.A. Katzenellenbogen, 1973). Acetylene itself can react with two molecules of an aldehyde or a ketone (V. jager, 1977). Hydration then leads to 1,4-dihydroxy-2-butanones. The 1,4-diols tend to condense to tetrahydrofuran derivatives in the presence of acids. 

The conjugate base of an alkyne is an alkyne anion (older literature refers to them as acetylides), and it is generated by reaction with a strong base and is a carbanion. It funetions as a nucleophile (a source of nucleophilic carbon) in Sn2 reactions with halides and sulfonate esters. Acetylides react with ketones, with aldehydes via nucleophilic acyl addition and with acid derivatives via nucleophilic acyl substitution. Acetylides are, therefore, important carbanion synthons for the creation of new carbon-carbon bonds. Some of the chemistry presented in this section will deal with the synthesis of alkynes and properly belongs in Chapter 2. It is presented here, however, to give some continuity to the discussion of acetylides. 

Because an alkyl group is added to the original alkyne molecule, this type of reaction is called an alkylation reaction. We limit our discussion in this chapter to reactions of acetylide anions with methyl and primary haloalkanes. We will discuss the scope and limitation of this type of nucleophilic substitution in more detail in Chapter 7. For reasons we will discuss there, alkylation of nucleophilic acetylide anions is practical only for methyl and primary halides. While this alkylation reaction can be used with limited success with secondary haloalkanes, it fails altogether for tertiary haloalkanes. 

Each alkyne can be synthesized by alkylation of an appropriate alkyne anion. First decide which new carbon-carbon bond or bonds must be formed by alkylation and which alkyne anion nucleophile and haloalkane pair is required to give the desired product. Synthesis of a terminal alkyne from acetylene requires only one nucleophilic substitution, and synthesis of an internal alkyne from acetylene requires two nucleophilic substitutions. 

Acid derivatives react with many nucleophiles by acyl substitution, including carbon nucleophiles. There are complications in this latter reaction because, in some cases, the compounds produced in the reaction are more reactive than the starting materials, and they compete for reaction with the nucleophiles. Experimentally, cyanide and alkyne anions are not the best partners in this reaction, so the focus will be on Grignard reagents and organolithium reagents. 

The reaction of carbon nucleophiles with ketones or aldehydes proceeds by acyl addition, as described in Chapter 18. The reaction of carbon nucleophiles with acid derivatives proceeds by acyl substitution, as described in Chapter 20. Carbon nucleophiles included cyanide, alkyne anions, Grignard reagents, organolithium reagents, and organocuprates. Alkyne anions are formed by an acid-base reaction with terminal alkynes (RC=C-H RCsCr). In this latter transformation, it is clear that formation of the alkyne anion relies on the fact that a terminal alkyne is a weak carbon acid. Other carbon acids specifically involve the proton on an a-carbon in aldehydes, ketones, or esters. With a siiitable base, these carbonyl compounds generate a new type of carbon nucleophile called an enolate anion. 

Anions of acetylene and terminal alkynes are nucleophilic and react with methyl and primary alkyl halides to form carbon-carbon bonds by nucleophilic substitution Some useful applications of this reaction will be discussed m the following section... 

The negative charge and unshared electron pair on carbon make an acetylide anion strongly nucleophilic. As a result, an acetylide anion can react with an alkyl halide such as bromomethane to substitute for the halogen and yield a new alkyne product. 

Alkynyl(phenyl)iodonium salts can be used for the preparation of substituted alkynes by the reaction with carbon nucleophiles. The parent ethynyliodonium tetrafluoroborate 124 reacts with various enolates of /J-dicarbonyl compounds 123 to give the respective alkynylated products 125 in a high yield (Scheme 51) [109]. The anion of nitrocyclohexane can also be ethynylated under these conditions. A similar alkynylation of 2-methyl-1,3-cyclopentanedione by ethynyliodonium salt 124 was applied in the key step of the synthesis of chiral methylene lactones [110]. 

Remember to work backward. The target ketone has five carbons, whereas the designated starting material has only three, so it is necessary to form a carbon-carbon bond. A nucleophilic substitution reaction can be done at C-l of 1-chloropropane. so a two-carbon nucleophile that can be ultimately converted to a ketone is required. A carbon-carbon bond-forming reaction that meets these requirements is the alkylation of an acetylide anion (see Section 10.8). Once the carbon-carbon bond has been formed, hydration of the alkyne can be used to convert the triple bond to a ketone ... 

Molander recognised the potential of the Sml2-mediated Barbier addition to esters for the initiation of sequential processes (Chapter 5, Section 5.4). Two types of cascade have been developed that involve nucleophilic acyl substitution the first type involves double intramolecular Barbier addition to an ester group (anionic-anionic sequences),17 and the second type consists of a Barbier addition to an ester followed by a carbonyl-alkene/alkyne cyclisation of the resultant ketone (anionic-radical sequences) (Scheme 6.12).18,19... 

Mechanistically, the one-pot transformation can be rationalized by a sequence of chemoselective coupling of ort/to-halogenated (hetero)aromatic acid chlorides 81 and electron rich terminal alkynes 4, followed by nucleophilic addition of the sulfide ion to the a,p-unsaturated system 86 to furnish the anionic Michael adduct 87, and finally an intramolecular nucleophilic aromatic substitution in the sense of an addition-elimination process concludes the sequence (Scheme 46). 

The substitution reactions of alkyl halides by carbon nucleophiles derived from alkynes and enolate anions provide major methods for the... 

Because acetylide anions are strong nucleophiles, the mechanism of nucleophilic substitution is S 2, and thus the reaction is fastest with CH3X and 1° alkyl halides. Terminal alkynes (Reaction [1]) or internal alkynes (Reaction [2]) can be prepared depending on the identity of the acetylide anion. 

The reason we ve discussed nucleophilic substitution reactions in such detail is that they re so important in organic chemistry. In fact, we ve already seen a number of substitution reactions in previous chapters, although they weren t identified as such at the time. For example, we said in Section 8.9 that acetylide anions react well with primary alkyl halides to provide the alkyne product. 

Alkynyl(phenyl)iodonium salts have found synthetic application for the preparation of various substituted alkynes by the reaction with appropriate nucleophiles, such as enolate anions [980,981], selenide and telluride anions [982-984], dialkylphosphonate anions [985], benzotriazolate anion [986], imidazolate anion [987], N-functionalized amide anions [988-990] and transition metal complexes [991-993]. Scheme 3.291 shows several representative reactions the preparation of Ai-alkynyl carbamates 733 by alkynylation of carbamates 732 using alkynyliodonium triflates 731 [989], synthesis of ynamides 735 by the alkyny-lation/desilylation of tosylanilides 734 using trimethylsilylethynyl(phenyl)iodonium triflate [990] and the preparation of Ir(III) a-acetylide complex 737 by the alkynylation of Vaska s complex 736 [991]. 

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