Halides, alkyl, reaction with alkyne anions

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. 

As noted above, alkyne anions are very useful in Sn2 reactions with alkyl halides, and in acyl addition reactions to a carbonyl.46 Alkyl halides and sulfonate esters (tosylates and mesylates primarily) serve as electrophilic substrates for acetylides. A simple example is taken from Kaiser s synthesis of niphatoxin B, in which propargyl alcohol (36) is treated with butyllithium and then the OTHP derivative of 8-bromo-1-octanol to give a 47% yield of 37.48... 

The real value of this acid-base reaction is to transform a weak acid into an anion by using a powerful base the organolithium reagent. Such anions behave as nucleophiles in various reactions. In Chapter 11 (Section 11.3.6), alkyne anions underwent Sn2 reactions with alkyl halides. In Chapter 18 (Section 18.3.2), alkyne anions react with aldehydes and ketones. Both Grignard reagents and organolithium reagents react as nucleophiles with aldehydes and ketones (also described in Chapter 18, Section 18.4). Lithium amides such as 45 react as bases with aldehydes or ketones in Chapter 22 (Section 22.3). Many such examples are discussed in this book. 

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. 

The new functional group exchange reactions presented in this chapter can be combined with reactions from previous chapters to expand the ability to synthesize molecules. Alkene 85 is synthesized from aldehyde 86, for example. The first task is to identify the four carbons of 86 in 85. It appears that the carbons marked in blue are the best candidates. Rather than disconnect the C-C=C unit marked in blue, first disconnect the ethyl group of 85 to give 87 and 88. This choice is made because no reaction has been presented that will allow direct incorporation of EtCHCH to X-C-CMea. Disconnection of the ethyl group takes advantage of the fact that an alkyne anion reacts with an alkyl halide. However, before this reaction can be used, the alkene unit in 87 needs to be changed to an alkyne unit in 89. 

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... 

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... 

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. 

The first alkyne cyclisations, from 377, 379 and 381, predate the early alkene cyclisations by a couple of years these three date from 1966173 and 1967,174 and illustrate the favourability of both exo and endo-dig cyclisation. All three generate benzylic vinyllithiums (378, 380 and 382), and both aryl (377, 379) and alkyl halides (381) are successful starting materials. Similar organomagnesium cyclisations were described at about the same time.175 However, it is not clear in these reactions how much of the product is due to participation of radicals in the mechanism - alkylbromides undergo halogen-metal exchange with alkyllithiums via radical intermediates (chapter 3).176 If it really is an anionic cyclisation, cyclisation to 378 is remarkable in being endo. Endo-dig anionic cyclisations are discussed below. 

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. 

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. 

In each step, the base NHg removes an sp hybridized proton, and the resulting acetylide anion reacts as a nucleophile with an alkyl halide to yield an Sn2 product. The first two-step reaction sequence forms the terminal alkyne A by nucleophilic attack of the acetylide anion on CHaBr. 

Three steps are needed to complete the synthesis. Treatment of HC CH with NaH forms the acetylide anion, which undergoes an Sn2 reaction with an alkyl halide to form a four-carbon terminal alkyne. Hydration of the alkyne with HgO, H2SO4, and HgS04 yields the target compound. 

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 ... 

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. 

Villieras and coworkers have contributed a considerable number of synthetic methods employing lithium halocarbenoids. An early example was the alkylation of dibromomethyllithium and higher homologs (Scheme 15). The anion (15) is easily generated from 1,1-dibromoalkanes by deprotonation with LDA in THF at low temperature. Alkenes can then be generated simply by treating the products with Bu"Li in EtjO, Alkylation of dichloromethyllithium with primary alkyl halides followed by reaction of the dichloroalkanes with Bu"Li represents a method for the preparation of 1 -alkynes. ... 

The alkynyl anion can act as a nucleophile. Reaction with primary alkyl halides will lead to alkylation (by an SN2 mechanism) and the introduction of an alkyl group on the terminal carbon atom of the alkyne. 

In Section 6.10, you saw that alkynes can be synthesized by the reaction of an acetylide anion with an alkyl halide. 

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