Coupling Glaser

Oxidative homocoupling of terminal alkynes using copper catalyst. 

Oxidative homo-coupling of terminal alkynes using copper catalyst in the presence of oxygen. 

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 111, Springer-Verlag Berlin Heidelberg 2009 

Gribble, G. W. Glaser Coupling. In Name Reactions for Homologations-Part / Li, J. J., Corey, E. J., Eds. Wiley Sons Hoboken, NJ, 2009, pp 236-257. (Review). 

The Glaser Coupling reaction describes the oxidative coupling of terminal 

Glaser originally invoked a copper phenylacetylide dimer (Ph-C=C-Cu-Cu-C=C-Ph) as the species that reacts with oxygen to form diphenyldiacetylene and Cu20. Subsequent studies by Salkind, Vaitiekunas, Bohlmann, and others provide further details on the mechanism of this alkyne coupling 

It should be noted that most presentations of the Glaser and related acetylene homocouplings show a simpler mechanism involving base-catalyzed formation of a copper(I) acetylide 8, oxidation to copper(ll) acetylide 9, and homocoupling of the resultant acetylenic radical 10 to afford 

Several minor variations and practical improvements on the Glaser and related acetylenic coupling reactions have been developed. For example, when Cul is substituted for CuCl in the standard Hay conditions (TMEDA, O2, acetone) a greatly improved yield of 12 is obtained, which was ascribed to the more soluble CuI-2TMEDA in acetone. The homocoupling of 2-ethynyl-l-methylpyrrole (13) only proceeds in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), which may be due to the decreased acidity of the acetylenic hydrogen.  

Glaser coupling can be carried out both in supercritical CO2 using NaOAc as base, e.g., 15 to 16, and in ionic liquids, e.g., 17 to 18. Likewise, water near its critieal point serves as a solvent for Glaser coupling. 

The mechanism of the Glaser coupling and related methods is very complex and is not fully understood. Studies revealed that the mechanism is highly dependent on the experimental conditions. The early proposal involving a radical mechanism has been rejected. The currently accepted mechanism involves dimeric copper(ll)acetylide complexes. 

Novel polymerizable phosphatidylcholines were successfully synthesized by the research team of G. Just. To prepare a 32-membered macrocyclic diyne, the Eglinton modification of the Giaser coupiing was utilized. The diester-diyne starting material was slowly added to a refluxing solution containing 10 equivalents of cupric acetate in dry pyridine. The macrocycle was isolated in 54% yield after column chromatography. 

During the biomimetic total synthesis of endiandric acids A-G by K.C. Nicolaou and co-workers, the key polyunsaturated precursor was assembled via the Giaser coupiing of two different terminal alkynes. One of the alkynes was used in excess so the yield of the heterocoupled diyne could be maximized. In a solvent mixture of pyridine methanol (1 1), the two reactant alkynes were treated with Cu(OAc)2 at 25 °C to provide the desired diyne in 70% yield. 

Wilcox and his research team designed and synthesized chiral water-soluble cyclophanes based on carbohydrate precursors. These compounds are also dubbed as glycophanes and they are potentially valuable enzyme models. The key macrocyclization step utilized the Glaser coupling and the reaction was carried out in a thermal flow reactor at 80 °C in 67% yield. 

Nucleoside dimers linked by the butadiynediyi group were prepared by A. Burger et al. using the Eglinton modification of the Giaser coupiing via dimerization of 3 -C-ethynyl nucleosides.  

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 119, Springer International Publishing Switzerland 2014 

Glaser, C. Ber. 1869, 2, 422 24. Carl Andreas Glaser (1841-1935) studied under Justus von Liebig and Adolph Strecker. He became a professor in 1869 when the Glaser coupling was discovered. He became the Chairman of the Board of BASF after WWI. 

Reproduced with permission from Schmidt R, Thorwirth R, Szuppa T, Stolle A. Ondruschka B, Hopf H. Fast, iigand- and solvent-free synthesis of 1,4-substituted Buta-1.3-diynes by Cu-cataiyzed homocoupling of tenvinal alkynes in a ball mill Chem Eur J 2011 17 8129-38. 

Cyclotrimerization side products in Glaser coupling of phenylacetylene. 

76 CHAPTER 2 Carbon-Carbon Bond-Forming Reactions 

Cross-coupling Glaser coupling of terminal alkynes. 

---

The Glaser coupling reaction is carried out in aqueous ammonia or an alcohol/ammonia solution in the presence of catalytic amounts of a copper-I salt. The required copper-II species for reaction with the acetylide anion R-C=C are generated by reaction with an oxidant—usually molecular oxygen. For the Eglinton procedure, equimolar amounts of a copper-II salt are used in the presence of pyridine as base. 

The dimerization of terminal alkynes, known as the Glaser coupling, the Eglinton coupling, and the Cadiot-Chodkiewicz coupling, is one... 

The alcohol 172 obtained by reaction of 86 with ethynyl magnesium bromide on oxidation with manganese dioxide gave the ketone 17361 Glaser coupling of the ketone 173 gave an equimolar mixture of the two acyclic diketones 170 and 174. 

Keywords acetylenic compound, CuCl2, Glaser coupling, diacetylenic compound... 

Keywords terminal alkyne, Glaser coupling, cupric chloride, microwave irradiation, butadiyne... 

The Glaser Coupling (or Hay Coupling) is a synthesis of symmetric or cyclic bisacetylenes via a coupling reaction of terminal alkynes. Mechanistically, the reaction is similar to the Eglinton Reaction the difference being the use of catalytic copper(I), which is reoxidized in the catalytic cycle by oxygen in the reaction medium. 

The related Hay Coupling has several advantages as compared with the Glaser Coupling. The copper-TMEDA complex used is soluble in a wider range of solvents, so that the reaction is more versatile. 

Macrocycle synthesis based on oxidative Glaser coupling suffers from the same handicap [20, 21] For example, Tobe s group investigated the synthesis and properties of diethynylbenzene macrocycles in great detail [22], The dimer unit 45 is ac-... 

Sanders and coworkers have shown that the interaction between pyridine and Zn-porphyrins can be used for controlling the outcome of the Glaser coupling of 62. They were able to show that ethynylphenyl-substituted Zn-porphyrins can be cyclodimerized or cyclotrimerized, depending on the specific pyridyl template present in the reaction medium [28], With 4,4 -bipyridene (63), the cyclodimer 64 was obtained in 70% yield, whereas the presence of 1,3,5 -tris (4-pyridyl) -triazine (65) supports the formation of the cyclotrimer 66 (50%) (Scheme 6.10). 

Scheme 6.20 Synthesis of a macrocyclic bissulfonate by template-supported Glaser coupling.

---