Alkynes reactions with alkyl halides

To date, many electrophilic reagents, such as alkyl halides, alkenes, alkynes, carbonyl compounds, epoxides, alcohols, and ethers, have been investigated in AFC alkylation reactions. On the other hand, the reactive 5-membered heteroaromatic compounds, such as indole, pyrrole, furan, and thiophene derivatives, and electron-rich benzene derivatives have been successfully applied in AFC alkylation reactions. Indole and pyrrole derivatives are most popular substrates due to their high reactivity and account for almost 80% of the published methodologies. A variety of chiral organometal-lic catalysts and organocatalysts are employed in the catalytic AFC alkylation reactions with high enantiomeric control. 

PROBLEM 10.65 Recall that terminal alkynes are among the most acidic of the hydrocarbons (p. 129), and that the acetylide ions can be used in 8 2 alkylation reactions with an appropriate aUgrl halide. For example. 

An acetylide ion can undergo an alkylation reaction with a methyl halide or a primary alkyl halide to form an alkyne. 

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... 

Reaction with Alkyl Halides The gas inlet tube is replaced by an addition funnel, and 10 ml of HMPT is added rapidly with stirring. The mixture is cooled to 10-15°, and a solution of the alkyl halide (0.1 mole) in 20 ml of THF is added dropwise over a period of 30-40 minutes. The mixture is then heated to 40° for 2-3 hours. The thick white suspension of the sodium halide is cooled and dilute cold hydrochloric acid is carefully added until the mixture is clear. The organic layer is separated, and the aqueous layer is extracted three times with 20-ml portions of ether, the ethereal extracts then being combined with the organic material. The ethereal solution is washed twice with saturated sodium chloride solution and dried. The ether and THF are removed under reduced pressure (rotary evaporator), and the alkyne is distilled. 

Alkyne alkylation is not limited to acetylene itself. Any terminal alkyne can be converted into its corresponding anion and then alkylated by treatment with an alkyl halide, yielding an internal alkyne. For example, conversion of 1-hexyne into its anion, followed by reaction with 1-bromobutane, yields 5-decyne. 

A microwave-assisted three-component reaction has been used to prepare a series of 1,4-disubstituted-1,2,3-triazoles with complete control of regiose-lectivity by click chemistry , a fast and efficient approach to novel functionalized compounds using near perfect reactions [76]. In this user-friendly procedure for the copper(l) catalyzed 1,3-dipolar cycloaddition of azides and alkynes, irradiation of an alkyl halide, sodium azide, an alkyne and the Cu(l) catalyst, produced by the comproportionation of Cu(0) and Cu(ll), at 125 °C for 10-15 min, or at 75 °C for certain substrates, generated the organic azide in situ and gave the 1,4-disubstituted regioisomer 43 in 81-93% yield, with no contamination by the 1,5-regioisomer (Scheme 18). 

Radical carbonylation reaction serves as a powerful tool for the synthesis of a range of carbonyl compounds. Radical carbonylation has been successfully applied to the synthesis of functionalized ketones from alkyl, aryl, and alkenyl halides.The radical aminocarbonylation reaction of alkynes and azaenynes provided efficient routes to 2-substituted acrylamides, lactams, and pyrrolidinones. For example, the aminocarbonylation of 4-pentyn-l-yl acetate 318 initiated by tributyltin hydride (Bu"3SnH) (30mol%) with AIBN (20mol%) gave acrylamide 325 in 92% yield (Scheme 43).A proposed mechanism starts from the addition of tributyltin radical 319 to alkyne... 

Alkyl halides undergo Sn2 reactions with a variety of nucleophiles, e.g. metal hydroxides (NaOH or KOH), metal alkoxides (NaOR or KOR) or metal cyanides (NaCN or KCN), to produce alcohols, ethers or nitriles, respectively. They react with metal amides (NaNH2) or NH3, 1° amines and 2° amines to give 1°, 2° or 3° amines, respectively. Alkyl halides react with metal acetylides (R C=CNa), metal azides (NaN3) and metal carboxylate (R C02Na) to produce internal alkynes, azides and esters, respectively. Most of these transformations are limited to primary alkyl halides (see Section 5.5.2). Higher alkyl halides tend to react via elimination. 

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. 

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). 

The reaction sequence in the vinylation of aromatic halides and vinyl halides, i.e. the Heck reaction, is oxidative addition of the alkyl halide to a zerovalent palladium complex, then insertion of an alkene and completed by /3-hydride elimination and HX elimination. Initially though, C-H activation of a C-H alkene bond had also been taken into consideration. Although the Heck reaction reduces the formation of salt by-products by half compared with cross-coupling reactions, salts are still formed in stoichiometric amounts. Further reduction of salt production by a proper choice of aryl precursors has been reported (Chapter III.2.1) [1]. In these examples aromatic carboxylic anhydrides were used instead of halides and the co-produced acid can be recycled and one molecule of carbon monoxide is sacrificed. Catalytic activation of aromatic C-H bonds and subsequent insertion of alkenes leads to new C-C bond formation without production of halide salt byproducts, as shown in Scheme 1. When the hydroarylation reaction is performed with alkynes one obtains arylalkenes, the products of the Heck reaction, which now are synthesized without the co-production of salts. No reoxidation of the metal is required, because palladium(II) is regenerated. 

If this Sn2 reaction is to produce a good yield, the alkyl halide must be an excellent SN2 substrate It must be methyl or primary, with no bulky substituents or branches close to the reaction center. In the following examples, acetylide ions displace primary halides to form elongated alkynes. 

Lewis acid-catalyzed reactions of readily ionizable alkyl halides with alkynes yield vinyl halides [207]. The regioselectivities of these additions can be rationalized by the relative stabilities of the intermediate vinyl cations. Unlike the situation described for additions to alkenes, there is no preference for anti-additions, and the stereoselectivities can be explained by the intermediacy of nonbridged species [208]. The site of nu-... 

Terminal alkynes are weakly acidic. The alkyne hydrogen can he removed by s strong base 9uch ae Na NH.. to yield nn a<%tylide anipn An acetylide anion ads as a nucleophile and can displace a halide ion from a primary alkyl halide in a n alkylation reaction. Acetylide anions are more stable iJian either alkyl anions or vinylic anions because their m ative charge is in a hybrid orbital with 50% s character, allowing the charge to be doser to the nucleus. 

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