Terminal acetylenes halides

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. 

Acetylenic Grignard reagents of the type RC CMgBr are prepared not from an acetylenic halide but by an acid-base reaction in which a Grignard reagent abstracts a proton from a terminal aUcyne... 

Similarly, the limitations and peculiarities of the cross-coupling of pyrazolyl-halides with terminal acetylenes have been fully and systematically studied by Russian chemists (86TH1 97TH1). 

Experiments with terminal acetylenes, isolation of an intermediate acetal, alkyne hydratation studies, and ab initio calculations provide substantiation of a unified mechanism that rationalizes the reactions in which the complex formation between the alkyne and the iron(III) halides is the activating step (Scheme 12) [27]. 

Table 4.7 Sonogashira coupling of aryl halides with terminal acetylenes in the presence of PdCbiPPhj) catalyst [120].

Cross-coupling of terminal acetylenes used as nucleophiles with aryl or alkenyl halides (referred to as the Sonogashira-Hagihara, or SH, reaction) is a versatile method of synthesis for acetylenic compounds, which are rapidly gaining importance as advanced new materials and building blocks for implementing unusual molecular architectures. 

Halopyridines, like simple carbocyclic aryl halides, are viable substrates for Pd-catalyzed crosscoupling reactions with terminal acetylenes in the presence of Pd/Cu catalyst. The Sonogashira reaction of 2,6-dibromopyridine with trimethylsilylacetylene afforded 2,6-bis(trimethylsilyl-ethynyl)pyridine (130), which was subsequently hydrolyzed with dilute alkali to provide an efficient access to 2,6-diethynylpyridine (131) [106]. Extensions of the reactions to 2-chloropyridine, 2-bromopyridine, and 3-bromopyridine were also successful albeit at elevated temperatures [107]. 

Coupling of allylic or piopargylic halides and terminal acetylenes can also be realized under completely catalytic conditions [204,205]. The reactions are carried out in aqueous medium in the presence of catalytic amounts of cqpper(I)halide. The hydrogen halide liberated in the reaction is neutralized with ammonia, an amine or alkali hydroxide. In many cases both the 1,1- and the 1,3-coupling product is obtained ... 

The Sonogashira reaction of 2-iodothiophene with 2-methyl-3-butyne-2-ol or trimethylsilylacetylene under phase transfer conditions using sodium hydroxide as base led to the formation of the expected products, which released their end group spontaneously under the applied conditions giving rise to the intermediate formation of 2-ethynylthiophene. This terminal acetylene, in turn, reacted with another molecule of aryl halide, yielding either non symmetrical or symmetrical diarylethynes. When 2-methyl-3-butyn-2-ol was used as acetylene equivalent68 it was possible to introduce a benzothiophene moiety in the second step, while the reaction of 2-iodothiophene and trimethylsilylacetylene led to the formation of l,2-bis(2 -thienyl)acetylene (6.47.),69... 

Acetylenic ketones.3 PdCl2(dppf) is generally the most satisractory catalyst for synthesis of acetylenic ketones by carbonylation of aryl and vinyl halides in the presence of a terminal acetylene. 

Group III and IV halides enhance the activity of chloroplatinic acid in hydrosi-lylation of phenylacetylene 455 whereas aluminum halides alone promote the addition of hydrosilanes to terminal acetylenes 456... 

Before discussing examples of the reactions, it should be pointed out that most types of vinylic halides used in this reaction are easily available. The UV-catalyzed addition of HBr to terminal acetylenes forms the 1-bromo-l-alkenes. The cis isomer is formed almost exclusively if the addition is carried out at dry ice temperature. The 2-bromo or 2-iodo-l-alkenes are obtained from reacting aqueous hydrogen halides with alkynes. The 2-substituted-1-bromo-l-alkenes are available by the bromination-base dehydrobromination reactions. 

Scheme 2. Mechanism of the Sonogashira reaction for Pd/ Cu-catalyzed cross-coupling of sp2-C halides with terminal acetylenes.

The Sonogashira cross-coupling reaction of terminal acetylenes with aryl or vinyl halides is a powerful tool for generation of carbon-carbon bonds between sp2- and sp-carbon. Numerous molecules of interest can be generated from a wide variety of aryl or vinyl halides (Scheme 3) [18-23],... 

Hydroboration of terminal acetylenes with boron halides permits the stereospecific synthesis of ( )-l-chloro(or bromo)alk-l-enes919. BBr3 adds to terminal acetylenes in a regio- and stereoselective manner to yield /Lhalovinylboranes, which are very useful syn-thons92a 923. B-bromo- and B-iodo-9 borabicyclo[3.3.1]nonane react similarly924"926. 

This is an indirect method to obtain an anti Markovnikov addition of HI to terminal acetylenes. Chlorination929 and bromination930 (with bromine or with sodium bromide931) of vinylboronic acids results in inverted vinyl halides. This allows the three-step stereospecific inversion of ( )vinyl bromide into the [Z] isomer (equation 137)932. 

Much of the new chemistry on the coupling of alkynyl halides has dealt mostly with applications of known methods. The Cadiot-Chodkiewicz-type coupling reactions (i.e. terminal acetylene coupling with alkynyl halides) have formed the cornerstone of synthesis of acetylenic retinoids (i.e. 9)58. 

K. Sonogashira, Development of Pd—Cu Catalyzed Cross-Coupling of Terminal Acetylenes with sp2-Carbon Halides, J. Organomet. Chem. 653, 46 49 (2002). 

Sonogashira K (2002) Development of Pd-Cu catalyzed cross-coupling of terminal acetylenes with sp -carbon halides. J Organomet Chem 653(l-2) 46 9... 

Hydrolysis yields the terminal acetylene (3) carbonation yields the propargylic acid (4). Synthesis of a wide variety of acetylenes is possible by the reaction of the intermediate lithium acetylides with other electrophiles (alkyl halides, aldehydes, ketones). 

Only alkylations of acetylenes (equation 128) are covered in this section, whereas the addition reactions of acetylenes to carbonyl compounds are not. Alkylation of a terminal acetylene is effected by the reaction of an alkyl or aryl halide with the... 

Very recently the alkylation of terminal acetylenes by vinyl aryl and heterocyclic halides was induced by Pd complexes under mild conditions. Use of palladium triphenylphosphine, PdCPPha), and a base, such as MeONa in DMF at 50-100 °C, gave high yields of disubstituted acetylenes (e.g. equation 161) . Other catalysts... 

---