Internal alkynes with alkyl halides

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. 

Lithium acetylide stabilized as its ethylenediamine complex is a very effective reagent in reactions with alkyl halides . DMSO is found to be the best polar solvent for its use (80-90% yields) but DMF is also satisfactory. These solvents have the advantage that the use of the inconvenient liquid ammonia is avoided. The reaction with iodo- and bromoalkanes requires lower temperatures (8 °C) than with chloroalkanes (25-35 °C). No internal alkynes or 1,2-dienes are formed . The lithium acetylide complex has also been used in the preparation of fluoroalkynes in DMSO (e.g. equation 129) . ... 

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. 

Brown et al [8] have devised a general, convenient, and simple synthesis of straight-chain alcohols from internal alkynes. Long-chain internal alkynes, prepared by Eiters procedure [9] by metalating 1-alkynes, followed by treatment with alkyl halides, are isomerized to 1-alkynes on treatment with potassium-3-aminopropylamide (KAPA) [10] in 1,3-diaminopropane (APA). KAPA is prepared by the quantitative reaction of potassium hydride with excess of (APA) [10]. This difunctional superbase produces exceptionally rapid migration of internal C=C to the terminal C=C position. The terminal alkynes thus obtained are subjected to dihydroboration with 2 equiv of 9-BBN. The dibora intermediate on alkaline hydrogen peroxide oxidation provides 61-80% yield (Table 6.4) [8] of the corresponding alcohols (Eq. 6.2). 

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. 

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. 

Based on these results, conditions for alkyl-Sonogashira coupling reactions were developed. Primary alkyl halides reacted with terminal alkynes catalyzed by 5 mol% of complex 24a and Cul in the presence of substoichiometric amounts of Nal for bromides or Bu4NI for alkyl chlorides (entry 29) [73]. The latter serves to catalyze the in situ generation of more reactive alkyl iodides under the reaction conditions. The internal alkyne products were isolated in 57-89% yield. The Sonogashira coupling can also be combined to the Kumada reaction described above. a,o)-Chloroalkyl bromides underwent the Kumada coupling first selectively... 

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. 

Part [1] Acetylene is converted to an internal alkyne B by forming two C-C bonds. Each bond is formed by treating an alkyne with base (NaNH2) to form an acetyiide anion, which reacts with an alkyl halide (C or D) in an Sn2 reaction (Section 11.11). 

The nucleophilic acetylide ion uses an electron pair to attack 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 alkyla-l tion because a new alkyl group has become attached to the starting alkyne. Alkyne alkylation is not limited to acetylene itself, Any terminal alkyne s can be converted into its corresponding anion and then alkylated by treat-j ment with an alkyl halide, yielding an internal alkyne. For example, con/ version of 1-hexyne into its anion, followed by reaction with 1-bromobutane,] yields 5-decyne ... 

Ne.xt ask, What is an immediate precursor of 2-bexyne WeVe seen that an internal alkyne can be prepared by alkylation of a terminal alkyne anion. In the present instance, we re told to start with 1-pentyne and an alky] halide. Thus, alkylation of the anion of 1-pentyne with iodomethane should yield 2-hexyne ... 

This method can be exploited as part of a one-pot hydroalkylation of an internal alkyne. Thus, titanium-catalyzed syn hydrozincation [24], followed by Negishi cross-coupling with an alkyl halide, stereospecifically generates a trisubstituted olefin (Eq. 8). 

Internal alkynes can be made from terminal alkynes by converting the terminal alkyne to an acetylide anion and then treating the anion with a primary alkyl halide. Propose a mechanism for the alkylation. (See Section 8.15.)... 

We can convert terminal alkynes into internal alkynes of any desired chain length, simply by choosing an alkyl halide with the appropriate structure. Just count the number of carbons in the terminal alkyne and the number of carbons in the product to see how many carbons are needed in the alkyl halide. 

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