Substitution alkyne anion

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. 

Two commonly used synthetic methodologies for the synthesis of transition metal complexes with substituted cyclopentadienyl ligands are important. One is based on the functionalization at the ring periphery of Cp or Cp metal complexes and the other consists of the classical reaction of a suitable substituted cyclopentadienyl anion equivalent and a transition metal halide or carbonyl complex. However, a third strategy of creating a specifically substituted cyclopentadienyl ligand from smaller carbon units such as alkylidynes and alkynes within the coordination sphere is emerging and will probably find wider application [22]. 

A related method was reported by Katritzky et al. [25], who prepared 1-alkoxy-l-(l,2,4-triazol-l-yl)allenes from the corresponding triazole-substituted alkynes, e.g. the reaction of 18 to 19 in Eq. 8.2. In this case the generated allenyl anion was trapped with methyl iodide. 

The radical anion of /3-trimethylsilylstyrene also undergoes dimerization but coupling takes place at the carbons a to silicon 33). The kinetics of the alkyne dimerization, followed by ESR, showed the reaction to be second order in radical anion 43). With Li+, Na+, K+, or Rb+ as the counterions, the rate increases in the order Si < C < Ge 45). Consistent with the increased stability of the trimethylsilyl-substituted radical anion, the radical anion of 1,4-bis(trimethylsilyl)butadiyne, produced by reduction with Li, Na, K, Rb, or Cs in THF is stable at room temperature even on exposure to air, whereas the carbon analog, 1,4-di-r-butyl-1,3-butadiyne radical anion, dimerizes by second-order kinetics at -40° (42). The enhanced stability of the trimethylsilylalkynyl radical anions has been attributed to p-drr interactions (42). 

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]. 

Alkynic intermediates serve as important functional groups in organic synthesis. Many important reactions exploiting the unique and versatile chemistry of the carbon-carbon triple bond have been devised over the last few years. A general strategy for the synthesis of substituted alkynes involves substitution and addition reactions of propargylic anion equivalents this approach is particularly well suited for the preparation of homopropargylic alcohols (Scheme 28). 

The most utilized method for alkylation of alkynes is via alkynylide anions. Their reaction with electrophilic reagents provides access to both terminal and internal alkynes as well as to functionally substituted alkynes. The higher electronegativity of carbon in the sp-hybridization state imparts relatively greater acidity to acetylene and 1-alkynes (pATa 24-26), so that bases such as alkyllithiums, lithium dialkylamides. 

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. 

For acceptor-substituted alkynes, it is possible to use trimethylsilyl azide as transfer reagent (cyanogen azide does not react). The reaction (2-90) is not regiospecific, but the silylated triazoles 2.225 can be hydrolyzed and deprotonated to the anion 2.226. The latter reacts regiospecifically with cyanogen bromide to form the triazole-carbonitrile 2.227, which is in equilibrium with the a-diazo-A -cy-ano-imine 2.228 (Regitz et al., 1981 b). 

This leads to di-C-substituted carbollide anions ( /This approach is of general use. Its major advantage is the avoidance of seeking for appropriate alkynes for the preceding closo-carboranes R,R C2BioHio. Especially for unsymmetrically C-substituted carboUides RC- and R C-vertices can be introduced in a very easy and systematic way. 

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]. 

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. 

As a replacement for alkynylanilines, Yamamoto has reported that indoles can he generated via the Pd(PPh3)4/CuCl-catalyzed coupling of 2-aIkynylaryUsocyanates with allylcarbonates (Scheme 6.18) [26]. In this case, fragmentation of the carbonate anion to an alkoxide upon oxidative addition to palladium allows conversion of the isocyanate into a carbamate for subsequent cydization. A number of substituted alkynes can participate in this reaction, and it can be performed with alcohols instead of allylcarbonates to form 3-unsubstituted indoles. A variant of this reaction involved the use of isocyanides in concert TMS-azide, providing a route to substituted N-cyanoindoles [27]. 

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. 

Acyl substitution of esters, acid chlorides, anhydrides with alkyne anions Grignard reagents organolithium reagents enolate anions... 

In the synthesis of propargylic alcohols, we saw the reaction of an alkynyl nucleophile (either the anion RC=CNa or the Grignard RC CMgBr, both prepared from the alkyne RC CH) with a carbonyl electrophile to give an alcohol product. Such acetylide-type nucleophiles will undergo Sn2 reactions with alkyl halides to give more substituted alkyne products. With this two-step sequence (deprotonation followed by alkylation), acetylene can be converted to a terminal alkyne, and a terminal alkyne can be converted to an internal alkyne. Because acetylide anions are strong bases, the alkyl halide used must be methyl or 1° otherwise, the E2 elimination is favored over the Sn2 substitution mechanism. 

High yields of alkynes can be obtained from the reaction of 1,1-dichloromethyl-lithium with alkyl halides and subsequent dehydro-halogenation. The alkyne anion (40) with alkyl halides gives a-substituted prop-2-ynylamines and with CO2 gives a-acetylenic amino-acids, in good yields. 

Terminal alkynes undergo the above-mentioned substitution reaction with aryl and alkenyl groups to form arylalkynes and enynes in the presence of Cul as described in Section 1.1.2.1. In addition, the insertion of terminal alkynes also takes place in the absence of Cul, and the alkenylpalladium complex 362 is formed as an intermediate, which cannot terminate by itself and must undergo further reactions such as alkene insertion or anion capture. These reactions of terminal alkynes are also treated in this section. 

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. 

M-substituted 2-pyridones can be prepared by N-alkylation, under basic conditions (pfCa of the amide proton is 11). The resulting anion can then react on either nitrogen or oxygen depending on the conditions employed [24-27]. Also, several direct methods for the construction of N-substituted 2-pyridones have been reported. Two such examples can be seen in Scheme 3 where the first example (a) is an intramolecular Dieckmann-type condensation [28] and the second (b) is a metal-mediated [2 -I- 2 + 2] reaction between alkynes with isocyanates [29,30]. 

Vinylic halides can react by a SrnI mechanism (p. 855) in some cases. An example is the FeCl2 catalyzed reaction of l-bromo-2-phenylethene and the enolate anion of pinacolone (t-BuCOCH2 ), which gave a low yield of substitution products along with alkynes. ... 

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