Lithium Acetylides

Synthetic Uses of Acetylenes

Second alkyation / acylation (4-Androstene-3,17-dione)

  

Reduction to form cis or trans double bond (Acutiphycin, Adaline, Pironetin)

  

Reduction to saturated chain - alkyllithium equivalent (Allopumiliotoxin, Indolizidine 223AB)

  

Hydrometalation to form vinyl organometallics; from them vinyl halides (Acanthoic acid, Nakienone B)

  

Hydroboration - oxidation to provide aldehyde enolate equivalent

  

Haloboration to give vinyl bromides, iodides (Deacetoxyalcyonin, Ipsenol)

  

Carbometalation to form vinyl organometallic (Codling Moth Compound, Dysidiolide, Okinellin-b)

  

Hydration to provide acyl anion equivalent (Cecropia-Juvenile-Hormone, LL-Z1271, Quadrone)

  

Numerous other main group and transition metal mediated reactions (e.g.: enyne metathesis)

Lithium Acetylides

Lithium acetylides are readily prepared by deprotonation of acetylenes using a variety of organmetallic bases to form Li (BuLi), Mg (iPrMgCl), Zn (NR3, Zn(OTf)) or other metal acetylides.

The high stability of the acetylide anion makes metal acetylides relatively poor nucleophiles. Thus additions to aldehydes and ketones are usually trouble-free, but less reactive carbonyl compounds and SN2 substrates such as alkyl halides and epoxides often react sluggishly and require harsh conditions, polar cosolvents like HMPA or DMSO, and/or Lewis acid catalysts.

Acetylenes can be introduced into molecules as nucleophiles, and this the usual approach. The reaction below illustrates a common subsequent transformation of the triple bond: reduction to an alkyne, which can be done with either cis or trans stereochemistry.

Acutiphycin: Smith, A. B.; Chen, S. S.-Y.; Nelsom, F.; Reichert, J. M.; Salvatore, B. A. J. Am. Chem. Soc. 1997, 119, 10935.

  
  
  
  
  
  
  

Acetylene Dianion Equivalents

  
  

Although acetylene can be deprotonated to form lithium and sodium acetylides, they are inconvenient to use, and there are some hazards in working with acetylene. Trimethylsilyacetylene or analogs are often used instead, since the silyl group can be readily cleaved under mild conditions. The acetylene "linchpin" strategy is illustrated below in a partial synthesis of Spongistatin

  
  
  
  
  

Other methods for the preparation of acetylenes

Conversion of Aldehydes to Acetylenes

Aldehydes can be converted acetylenes using several methods. Most commonly used is the Corey-Fuchs reaction, followed by a Fritsch-Buttenberg-Wiechell rearrangement. The example below illustrates a very powerful follow-up transformation of the triple bond, a hydrozirconation-bromination sequence.

  

Metalated trimethylsilyldiazomethane will also convert aldehydes to acetylenes.

Pareitropone: Feldman, K. S.; Cutarelli, T. D. J. Am. Chem. Soc. 2002, 124, 11600

  

Diazo Horner-Wadsworth-Emmons reagent (Müller, Liepold, Roth, Bestman Synlett. 1996, 521):

Anatoxin A: Brenneman, G. B.; Martin, S. F. Org. Lett. 2004, 6, 1329

  
  

This reaction works by an initial base-catalyzed deacylation of the diazophosphonate, followed by a similar rearrangement of the vinylidene.

  

Reaction of Allenyl/Propargyl-organometallic Reagents with Electrophiles

Allenyl organometallic reagents often react with carbonyl compounds to give propargyl products, although allenyl products can also be obtained.

In the partial synthesis of Quadrone below the propargyl/allenyl anion behaves as an acetonyl anion (acetone enolate) equivalent: Takeda, K.; Shimono, Y.; Yoshii, E. J. Am. Chem. Soc. 1983, 105, 563.

  

(-)-Ipsenol: N. Ikeda, A. Arai, H. Yamamoto, J. Am. Chem. Soc., 1986, 108, 483

  

The product allenyl/propargyl selectivity can sometimes be controlled by proper choice of metal:

Controlling Allenyl-Propargyl Selectivity: Azetidinediones: Alcaida, Almendros, Aragoncillo, Rodriguez-Acebes J. Org. Chem. 2001, 66, 5208.

  

The dliithium reagent prepared by deprotonation of allene often forms propargyl products when used in SN2 reactions. The alkynyl lithium reagent formed can be used with a second electrophile. (? Chem. Commun. 1975, 817)

Isosteviol: Snider, B. B.; Keselgof, J. Y.; Foxman, B. M. J. Org. Chem. 1998, 63, 7945

  

7-Hydroxymyoporone: Reich, Shah, Gold, Olson J. Am. Chem. Soc.., 1981, 103, 3112

  

Isomerization of Acetylenes

Acetylenes are prone to isomerization reactions, which can interconvert acetylenes and the related allenes. A particularly useful one is the isomerization of internal to terminal acetylenes, driven by the higher stability of the alkynyl anion.

Patchouli Alcohol: Magee, T. V.; Stork, G.; Fludzinski, P. Tet. Lett. 1995, 36, 7607

  

Trifarienols: Huang, H.; Forsyth, C. J. J. Org. Chem. 1995, 60, 5747.

  

Web page created by WINPLT (c) Hans J. Reich, 2004, All Rights Reserved