Acetylides reactions with alkyl halides

Finally, acetylide anions have been alkylated with propargyl halides to give excellent yields of dialkynes643,644. Similar reactions have been used in the synthesis of a wide variety of natural products including lactones and macrolides645,646 and leukotrienes647-651. With many halides, reaction with acetylide anions is not useful however, due to elimination side-reactions caused by the significant basicity of the carbanion. 

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. 

We have already learnt that alkyl halides react with alcohols and metal hydroxide (NaOH or KOH) to give ethers and alcohols, respectively. Depending on the alkyl halides and the reaction conditions, both S l and Sn2 reactions can occur. Alkyl halides undergo a variety of transformation through Sn2 reactions with a wide range of nucleophiles (alkoxides, cyanides, acetylides, alkynides, amides and carboxylates) to produce other functional groups. 

Step [3] B is prepared from acetylene and two 1 alkyl halides (C and D) by using Sn2 reactions with acetylide anions. 

Now that you know that this is an 8 2 reaction (the alkyl halide reacts with a high concentration of a good nucleophile), you can understand why it is best to use primary alkyl halides and methyl halides in the reaction. These alkyl halides are the only ones that form primarily the desired substitution product. A tertiary alkyl halide would form only the elimination product, and a secondary alkyl halide would form mainly the elimination product because the acetylide ion is a very strong base. 

The proton of terminal acetylenes is acidic (pKa= 25), thus they can be deprotonated to give acetylide anions which can undergo substitution reactions with alkyl halides, carbonyls, epoxides, etc. to give other acetylenes. 

The major limitation to this reaction is that synthetically acceptable yields are obtained only with methyl halides and primary alkyl halides Acetylide anions are very basic much more basic than hydroxide for example and react with secondary and ter tiary alkyl halides by elimination... 

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... 

Reactions in liquid ammonia (cf. Chapter 3, Section III) require a certain amount of care, since the solvent is low boiling (—33 ) and its fumes are noxious. Nevertheless, with reasonable caution, the preparation of an ammonia solution of sodium acetylide can be carried out as described. The reagent so prepared can then be directly used for displacements on alkyl halides or for additions to suitable carbonyl compounds. Examples of both reactions are given. 

The alkylation reaction is limited to the use of primary alkyl bromides and alkyl iodides because acetylide ions are sufficiently strong bases to cause dehydrohalogenation instead of substitution when they react with secondary and tertiary alkyl halides. For example, reaction of bromocyclohexane with propyne anion yields the elimination product cyclohexene rather than the substitution product 1-propynylcyclohexane. 

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. 

Here too, a second alkylation can be made to take place yielding RC=CR or R C=CR. It should, however, be remembered that the above carbanions—particularly the acetylide anion (57)—are the anions of very weak acids, and are thus themselves strong bases, as well as powerful nucleophiles. They can thus induce elimination (p. 260) as well as displacement, and reaction with tertiary halides is often found to result in alkene formation to the exclusion of alkylation. 

All acetylenes with a terminal triple bond are instantaneously converted into the alkali acetylides by alkali amides in liquid ammonia. For many alkylations with primary alkyl halides liquid ammonia is the solvent of choice and the functionalization with oxirane can also be carried out in it with good results. Reactions of ROOM with sulfenyladng agents (R SSR1, R SON, R SSC R ) or elemental sulfur, selenium or tellurium are mostly very successful in ammonia, the same holds for the preparation of ROC1 from RC=CM and iodine. The results of couplings with carbonyl compounds are very variable. 

Compared to many other types of synthetic intermediates, acetylides, RC=CM (M = Li, Na, K), show a moderate reactivity towards alkyl halides in the usual organic solvents E O and THF and in liquid ammonia [2], In this respect acetylides resemble enolates >C=COM. In the absence of dipolar aprodc co-solvents (DMSO or HMPT), lithium alkynylides, RC=CLi, react sluggishly in Et O or THF with most alkyl halides [2]. In liquid ammonia the alkylation of alkali acetylides with the lower (up to C-5) alkyl bromides or iodides proceeds at a satisfactory rate [5]. A certain amount of DMSO added to the reaction mixture increases the solubility of halides with a longer carbon chain. A second effect of the addition of this co-solvent is that the temperature of the reaction mixture can gradually rise as more ammonia evaporates. In this way, the reaction can proceed gradually over the range from -33 C (b.p. NH3) to room temperature. Specific alkylation on the acetylenic carbon takes place if an equivalent amount of an alkyl halide is added to dilithiated propargvl alcohol in liquid ammonia... 

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. 

Under the same conditions simple etiolates react vigorously with alkyl halides (which must be primary) to give mono- and polyalkylated products. The reactivity of the simple enolate is greater and cannot be controlled at room temperature. However, if the alkylation is carried out at low temperature, the reaction can be controlled and smooth monoalkylation of simple enolates can be achieved. The same is true for the alkylation of acetylide anions, which must be carried out at low temperature for successful alkylation. 

Longer-chain alkyl halides may not be commercially available, but they are readily made in one step from the corresponding alcohols (Larock, 1999), as are tosylates and mesylates. Similarly, longer-chain terminal alkynes are not commercially available, but can be readily made by reaction of alkyl halides with lithium acetylide-ethylene diamine complex in dry... 

Primary alkyl halides can also be alkynylated by silver acetylides. Isabelle and coworkers reported the reaction of methyl iodide, ethyl iodide and <7rmethyl iodide with several silver acetylides to give disubstituted alkynes.116 The authors preferred a non-radical-mediated mechanism for this reaction, as neither methane nor ethane, expected byproducts of a radical reaction, were observed. 

The reaction of an acetylide ion with a primary alkyl halide allows the synthesis of di-substituted alkynes [Following fig.(a)]. 

For the preparation of the second component 421 of the cockroach pheromone Burgsthaler et al. 228) also used a Wittig reaction. Lithium acetylide is alkylated with the two halides 414 and 416 and the resulting alkynyl bromide 417 converted into the phosphonium salt. Olefination of the corresponding ylide with 9-bromo-2-nonanone 418 gives a (Z)/( )-mixture of olefin 419 which is converted into the pheromone 3,ll-dimethyl-29-hydroxynonacosan-2-one 421 by aeetoaeetate synthesis, hydrogenation, hydrolysis, and decarboxylation 228) (Scheme 73). 

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