DIssolving Metal Reductions

Transition Metal Reductants:
Reductions Promoted by Low Valent Transition Metal Complexes in Organic Synthesis,
   Pons, J. M.; Santelli, M. Tetrahedron 1988, 44, 4295.
The Application of Low-valent Titanium Reagents in Organic Synthesis,
   Lenoir, D. Synthesis 883.

  There are a number of metals at the zero or low oxidation state that readily donate one or more electrons to molecules with an accessible LUMO orbital (Li°, Na°, K°, Zn°, Mg°, Ca°, Cr+2, Ti°, Sm+2, etc). These function primarily as electon transfer reagents, although the transition metals and lanthanides also have a strong component of sigma bonding between cations and intermediate anions. Some typical reduction scenarios are outlined below. The initial process is usually an electron transfer to form a radical anion. This may be the end of the process, or a second electron transfer may occur to form a dianion. Alternatively, the radical anion can be protonated if there is a proton source available, or it may fragment if there is a leaving group (X) present. In each case a radical is formed, which can then be reduced a second time, and protonated if there is a sufficiently acidic proton source present. In favorable circumstances the final anion accumulates in the reaction, and can be trapped with electrophiles (E+) other than protons (e.g. alkylation).


Birch Reduction

The Metal-Ammonia Reduction of Aromatic Compounds,
   Rabideau, P. W. Tetrahedron 1989, 45, 1579.
The Birch Reduction of Aromatic Compounds,
   Rabideau, P. W.; Marcinow, Z. Org. React. 1992, 42, 1.
The Birch Reduction of Steroids. A Review,
   Pellissier, H.; Santelli, M. Org. Prep. Proced. Intern. 2002, 34, 609, 611-42.
Birch Reduction and its Application in the Total Synthesis of Natural Products,
   Subba Rao, G. S. R. Pure. Appl. Chem. 2003, 75, 1443-51.

  The Birch reduction (Birch, A.J.; Smith, H. Quart. Rev. (London), 1958, 12, 17.) of aromatic compounds involves reaction with a solution of lithium or sodium in ammonia, basically solutions of M+ e-. Usually a proton donor such as t-butanol or ethanol is present to avoid the buildup of very basic LiNH2, which can be harmful to the integrity of the products. The major product is normally a 1,4-diene, resulting from protonation of the intermediate pentadienyl anion at the center carbon, which bears the highest electron density. Substituted benzenes lead to 1,4-cyclohexadienes with the more highly substituted double bonds


  If Birch reductions are run without an alcohol proton source, the basic LiNH2 formed can cause double bond isomerization, and over-reduction (Rabideau JOC 1983, 48, 4266).


  The Birch reduction of methoxybenzenes is a useful synthesis of cyclohexenones: Desogestrel: Corey, E. J.; Huang, A. X. J. Am. Chem. Soc. 1999, 121, 710. Note that the isolated double bond is not reduced.


  Benzoic acids are reduced to form the cross-conjugated carboxylate dianion, which can be alkylated to form 1-substituted cylohexadienecarboxylic acids. Fichtelite: Taber, D.F, Saleh, S. A. J. Org. Chem. 1980, 102, 5085


Reduction of Enones to Enolates

  Under typical Birch reduction conditions α,β-unsaturated enones and carboxylic esters are reduced to enolates, which can be trapped regiospecifically by reactive alkylating agents or other electrophiles. Upial:Taschner, M. J.; Shahripour, A. J. Am. Chem. Soc. 1985, 107, 5570.


  The reduction of double bonds in bicyclo[4.4.0] systems will usually give the trans-fused ring system (Stork J. Am. Chem. Soc., 1960, 82, 1512). Acanthoic Acid: Ling, T.; Chowdhury, C.; Kramer, B. A.; Vong, B. G.; Palladino, M. A.; Theodorakis, E. A. J. Org. Chem. 2001, 66, 8843


Hispidospermidine: Frontier, A. J.; Raghavan, S.; Danishevsky, S. J. J. Am. Chem. Soc. 2000, 122, 6151.


Reductive Dimerization of carbonyl compounds - Pinacol and McMurry reductions

Carbonyl-coupling Reactions Using Low-valent Titanium,
  McMurry, J. E. Chem. Rev. 1989, 89, 1513.
Carbonyl Coupling Reactions Using Transition Metals, Lanthanides and Actinides,
  B. E. Kahn and R. D. Riecke, Chem. Rev. 1988, 88, 733.
New Developments in the Chemistry of Low-Valent Titanium,
  Furstner, A.; Bogdanovic, B. Angew. Chem. Int. Ed. Engl. 1996, 35, 2442-69.
Catalytic, Highly Enantio- and Diastereoselective Pinacol Coupling Reaction with a New Tethered Bis(8-Quinolinolato) Ligand.
  Schmidt, D. R. Chem. Tracts 2005, 18, 52-6.


  McMurry developed a reduction procedure that is more reliable than the Mg pinacol conditions using the much more oxophilic metal titanium. The reagent, thought to be a mixture of Ti(0) and Ti(II) species, is usually formed by reduction of TiCl3 with Zn/Cu, although other reductants such as LiAlH4, potassium-graphite (C8K), Zn, and Mg can be used. The reagent is most useful for intramolecular reductions to form cyclic glycols and alkenes, but can also perform high-yield cross-coupling of aldehydes and ketones if one reactant can be present in excess. The reaction can be stopped at the diol stage, as in the Sarcophytol and Taxol examples below, but under more vigorous conditions a second reduction to an alkene occurs.

Sarcophytol B: McMurry, Tetrahedron Lett., 1989, 30, 1173.


Formation of 8-membered ring in Taxol synthesis: Nicolaou, Nature, 1994, 367, 630.


Use of Samarium iodide: Taxol Model: Swindell, Fan Tetrahedron Lett. 1996, 37, 2321.


Compactin: Clive, J. Am. Chem. Soc., 1990, 112, 3018.


Vetispirene: Paquette, L. A.; Yan, T. H. Tetrahedron Lett. 1982, 23, 3227


(±)-δ-Araneosene: Hu, T.; Corey, E. J. Org. Lett. 2002, 4, 2441


Acyloin Reduction

  Treatment of carboxylic esters with metallic sodium under aprotic conditions leads to a reductive dimerization to α-hydroxyketones (acyloins). The reaction is best done in the presence of trimethylsilyl chloride, which traps the intermediate enolates. The reaction is especially useful for the formation of rings.


Electron Reduction of C-X Bonds

  Treatment of C-X compounds with dissolving metal reductants (where X is some reasonably good leaving group such as Cl, Br, I, OSO2R, OP(O)(OMe)2, OP(O)(NMe3)2, OAc, SPh, SePh, SO2Ph) can lead to reductive cleavage of the C-X bond and formation of a C-M bond, which can be protonated or used for further reactions. This is the most common way to make organolithium and organomagnesium reagents.

  If there is a sufficiently acidic proton source in the medium, the organometallic reagent C-M will be protonated to form C-H. Reactions of this type are especially facile for X substituents α to carbonyl groups and those at allylic and benzylic positions (removal of benzyl protecting groups) because of the conjugative stabilization of the intermediate radical and anion, but reductions can be performed even of unactivated C-X bonds.

  Common reagents are Zn/Cu (activated zinc), Mg/ether, Li/THF, Li/NH3, Na/NH3, Na(Hg), Al(Hg), Na/EtOH, SmI2. Lithium in ether solvents can be activated by the presence of a catalytic amount of an arene (naphthalene and 4,4'-di-t-butylbiphenyl are common ones). In this case the aromatic radical anion or dianion is the active reducing agent.


  Reduction of Ketones to Alkenes. The conversion of ketones to alkenes can be achieved by conversion to enol phosphate or amidate, followed by dissolving metal reduction. In the first example below two reductions, the first of an enone and the second of an enol phosphate, are used to convert an α,β-unsaturated ketone to an alkene. In the second the enolate intermediate in the enone reduction is trapped to form a phosphate, which is then reductively cleaved.

β-Elemenone: Majetich, G.; Grieco, P. A.; Nishizawa, N. J. Org. Chem. 1977, 42, 2327.


Cuauhtemone: Goldsmith, D. J.; Sakano, I. J. Org. Chem. 1976, 41, 2095.



  Metalated sulfones have a number of important applications in synthetic chemistry, including alkylations, acylation, and condensation with ketones and aldehydes (Julia olefination ). The sulfonyl group is often reductively removed during the process, or needs to be removed after the task is done. Buffered sodium or aluminum amalgam are commonly used reagents.

Zizaene: Piers, E.; Banville, J. Chem. Commun. 1979, 1138


Reduction of Acetylenes

Alkynes are reduced to trans alkenes under dissolving-metal conditions:

Pironetin: Dias, L. C.; Oliveira, L. G.; Sousa, M. A. Org. Lett. 2003, 5, 265


There are several ways to perform the cis-reduction of alkynes:

Hydroboration-protonation - Dehydroarachidonic Acid.: Corey, E. J.; Kang, J. Tetrahedron Lett., 1982, 23, 2651.


Lindlar reduction - Japonilure: Papillon, J. P. N.; Taylor, R. J. K. Org. Lett. 2002, 4, 119