[7439-93-2]  · Li  · Lithium  · (MW 6.94)

(powerful reducing agent;1 used for partial reduction of aromatics and conjugated polyenes;1e,m-o conversion of alkynes to trans-alkenes;1a,h stereoselective reduction of hindered ketones;1l enone reduction and regioselective alkylation;1f,j reductive cleavage of polar single bonds1a)

Physical Data: mp 180.5 °C; bp 1327 ± 10 °C; d 0.534 g cm-3. Natural isotopic composition: 7Li (92.6 %); 6Li (7.4 %).

Solubility: 10.9 g/100 g NH3 at -33 °C (= 74.1 g/L NH3); 36.5 g/L MeNH2 at -23 °C.

Form Supplied in: under Ar, as solid in the form of wire, ribbon, rod, foil, shot, ingot, or as a powder; in mineral oil, as wire, shot, or as 25-30 wt % dispersions.

Purification: commercially available in up to 99.97% purity. In general, lithium is not further purified except for cutting off the surface coating.

Handling, Storage, and Precautions: best stored under mineral oil in airtight steel drums and handled under Ar or He. Dispersions in mineral oil segregate on storage and uniformity is restored by stirring. The mineral oil is washed off under Ar with pentane or hexane, and the metal is either dried in an Ar stream or rinsed with the reaction solvent. Dry Li powder is extremely reactive towards air, H2O vapor, and N2. The metal reacts rapidly with moist air at 25 °C, but with dry air or dry O2 only at higher temperatures (>100 °C). A slight blow can initiate violent burning. Reaction with N2 already occurs at 25 °C, but is inhibited by traces of O2. Li reacts readily with H2O, but does not spontaneously ignite as the other alkali metals do. It reacts rapidly with dil HCl and H2SO4 and vigorously with HNO3. Ready reaction occurs with halogens.

Reducing Systems.

For reductions with Li, liquid Ammonia or primary amines are most often the solvents of choice. Li dissociates in these solvents more or less completely into Li+ and solvated electrons, producing deep-blue metastable solutions.2 Ethereal solvents (peroxide-free!) such as THF or DME may be used alone, but are usually used as cosolvents with NH3 or amines. Li solutions in HMPA are quite unstable in contrast to Sodium solutions, but are stabilized by THF.3 Reduction occurs by a sequence of single electron and proton transfers to the organic substrate, leading to saturation of multiple bonds or fission of single bonds.1a,i,4


Li has a higher normal reduction potential5 and molar solubility6 in liquid NH3 than Na or Potassium (see Table 1). This permits the use of larger quantities of cosolvents for substrates that are less soluble in NH3. The concentrations of Li in NH3 used in reactions vary widely, from 0.1 to 3 g Li/100 mL NH3. Concentrations near saturation form a second, less dense, bronze-colored phase which is normally avoided.7

Reductions are performed either in the absence or presence (Birch conditions1h) of a proton source, depending on the desired products.1a,i,4b An added proton source can effect reductions which do not occur in its absence (e.g. benzene reduction). It can lead to higher saturation (e.g. in enone reduction) or suppress dimerization and base-catalyzed transformations of primary products. EtOH and t-BuOH are the most common proton donors. Primary alcohols protonate the intermediate anions more rapidly, but tertiary alcohols react more slowly with the metal. Other proton donors are NH4Cl, H2O, and various amines.1a,e,4b

The order of adding the reagents can influence the product distribution.1g Most often, Li is added last, until the blue color of the solution persists. For less reactive substrates, alcohol addition is delayed (Wilds-Nelson modification).5b The reaction is concluded by quenching excess Li mildly and efficiently with sodium benzoate8 or with excess EtOH and then NH4Cl, and NH3 is allowed to evaporate.

Distillation of NH3 from Na or through a BaO column removes moisture and iron impurities. The latter catalyze the reaction of alkali metals with the added alcohol and NH3.2 The Li-NH3-ROH system is less sensitive to traces of iron than Na-NH3-ROH, which accounts in many instances for its superiority.9 Lithium Amide is less soluble in NH3 than Sodium Amide and Potassium Amide, and base-catalyzed formation of side products is less frequent.1g,i Nevertheless, in many cases similar results are obtained with Li and Na in NH3; Li is preferred for less reactive substrates and Na when overreduction is a problem.1

Lithium/Primary Amines.

Li forms stronger, but less selective, reducing agents with primary amines (Benkeser reduction).1d,h,k The higher reactivity is probably caused by higher reaction temperatures1i,k and possibly also by smaller electron solvation.2 The reactivity can be modified by addition of alcohols.1h The Li-amine solutions seem more sensitive to catalytic decomposition than Li in NH3.10 The choice of the amine is limited by the solubility of Li; ethylamine and ethylenediamine are most common. Na is hardly soluble in amines (e.g. more than 100 times less soluble in ethylenediamine at room temperature than Li).11 Reactions of calcium in amines have been described.12

Reduction of Aromatic Compounds.1,13

Benzene and its derivatives are reduced to 1,4-cyclohexadienes with Li-NH3 in the presence of a proton source (see also Sodium-Ammonia). Derivatives with electron-donating substituents lead to 1-substituted cyclohexadienes. Thus reduction of anisole derivatives furnishes 1-methoxycyclohexa-1,4-dienes (eq 1).9

Hydrolysis of such dienol ethers to cyclohex-3-enones or with isomerization to cyclohex-2-enones has found wide application in syntheses of steroids, terpenoids, and alkaloids.1f,m Li is superior to Na for the more difficult reductions of 1,2,3-substituted anisole derivatives,5b though sometimes even excess Li gives poor results.14 Anisoles are more readily reduced than phenols (eq 2),15 but higher concentration of Li in NH3 may effect phenol reduction to cyclohexenols (eq 3).16

Electron-acceptor substituents enhance reduction rates and promote 1,4-reduction at the substituted carbon atoms, irrespective of alkoxy, amino, or alkyl substituents. Benzoic acid derivatives are readily reduced to the 1,4-dihydro derivatives. The presence of an alcohol is not necessary, in contrast to the derivatives with electron-releasing substituents. It can even result in overreduction, as the lithium alcoholate facilitates isomerization of the 1,4-dihydro product to the 3,4-dihydro isomer (eq 4).17

The dienolate formed during the reduction can be alkylated in situ with alkyl halides,18,19 epoxides,19 or a,b-unsaturated esters (eq 5)20 to give 1-substituted dihydrobenzoic acids. Rearomatization provides alkyl-substituted aromatic compounds.

Benzamides and alkyl benzoates can be reduced to the 1,4-dihydro amides and esters, respectively, with Li-NH3-t-butanol, but K-NH3-t-butanol appears superior.13 However, Li may be better for in situ reductive alkylations, or K+ may be exchanged with Li+ before the alkylation step.21 Reductive methylation of N-benzoyl-L-prolinol derivatives afforded excellent diastereoselectivities, irrespective of the use of Li, Na, or K (eq 6).22

The strongly activating and easily removable trimethylsilyl group has been used to direct the regioselectivity of reduction (eq 7).23

The Li-amine-alcohol reagents also reduce benzene derivatives to cyclohexadienes, and are usually applied when reduction in NH3 fails.1h,k Thus reduction of dehydroabietic acid with Li-NH3-t-BuOH afforded 35% of diene while Li-EtNH2-t-C5H11OH gave 81% (eq 8).24 The importance of the nature of the proton source is demonstrated by the fact that neither Li-NH3-EtOH nor Li-EtNH2-EtOH gave any appreciable amount of reduction product.

Reduction with Li-amine gives mainly cyclohexenes due to isomerization of the initially formed 1,4-diene by the strong alkylamide base.1h,i Mixtures of regioisomers are formed, and best results favoring the most stable isomer are obtained with mixtures1h of primary and secondary amines (eq 9).25

Condensed aromatic hydrocarbons are reduced more easily than those in the benzene series. Carefully chosen reaction conditions lead to the selective formation of different products.1b Most extensive reductions are achieved with Li-ethylenediamine,26 while Na-NH3 is one of the mildest reagents.27 Birch and Slobbe discuss the reduction of heterocyclic aromatics.4b

Lithium-induced cyclization of 1,1-binaphthalenes followed by oxidation of the dianion affords perylenes.28 3,10-Dimethylperylene was obtained in 95% (eq 10a).28a Cyclizations to tetrasubstituted perylenes proceeded in 36-40%,28b while similar reactions with K seem somewhat higher yielding.29a However, the synthesis of an 1-alkylated perylene was only successful with Li (eq 10b).29b

Reduction of Alkynes.1b,h

Internal alkynes are reduced to trans-alkenes with Li-NH3 or stoichiometric amounts of Li in amines. Excess Li in amines leads to alkanes. Li-EtNH2-t-BuOH efficiently reduced an alkyne precursor of sphingosine to the trans-alkene with simultaneous N-debenzylation, while triple bond reduction was incomplete with Na-NH3 and Li-NH3 (eq 11).30

Dissolving metal reduction is the method of choice for the reduction of triple bonds in the presence of nonconjugated carboxyl groups,31 where Lithium Aluminum Hydride4 in THF fails. Li-NH3 afforded higher amounts of trans-alkenes in the reduction of some cyclic alkynes compared with Na-NH3.32 Terminal triple bonds are protected against reduction with Li-NH3 by deprotonation with alkali amide, but are completely reduced to double bonds by Li (or Na)-NH3-(NH4)2SO4 or by Li in amines.1c Suitably located carbonyl groups give rise to cyclization, yielding vinylidenecycloalkanols,33 e.g. eq 12.33a However, the use of K33a,34a or electrochemical reduction34b may give better results.

Reduction of Ketones.1a,b,l,35

Li-NH3-EtOH reduces sterically hindered cyclic ketones to equatorial alcohols (eq 13)36 and has been widely applied in the syntheses of 11a-hydroxy steroids.37 This method is complementary to complex hydride reductions, which mainly afford the axial alcohols. Bicyclo[2.2.1]heptanones are reduced predominantly to the endo-alcohols. Similar results have been found with Na, K, and Ca.35

a,b-Unsaturated ketones are reduced to the ketone by Li-NH3.1j In fused ring enones the relative configuration at the ring junction is determined by protonation at the b-carbon.38 Regioselective alkylation is achieved by trapping the intermediate enolate with an alkyl halide,39a a strategy also applied to enediones (eq 14).39b In the presence of a proton source, reduction to the saturated alcohols occurs.40 Li-EtND2-t-BuOD reduction gives high yields of saturated ketones and has been used for the stereoselective deuteriation at the b-carbon.41 Conversion to alkenes is accomplished by phosphorylation of an enolate formed by Li-NH3 reduction and subsequent hydrogenolysis with Li-EtNH2-t-BuOH (eq 15).42

Reductions of aromatic ketones are complicated by possible pinacol formation, reduction of the aromatic ring, and hydrogenolysis of the C-O bond. Depending on the reaction conditions, 1-tetralone is reduced to tetralin or 1-tetralol (eq 16);43a in fact, seven different products can be produced.43b

Aromatic aldehydes and ketones are alkylated and deoxygenated in a one-pot procedure using alkyl- or aryllithium, followed by Li-NH3 (eq 17).44

Aliphatic Carboxylic Acids.

Simple straight chain carboxylic acids are reduced by Li-MeNH2 or Li-NH3 to an intermediate imine which can either be hydrolyzed to the aldehyde or catalytically reduced to the amine.45

Reductive Cleavage of Polar Single Bonds.1a

Li in various solvents provides effective reagents for the cleavage of polar single bonds. The cleavage tendency decreases in the order C-I > C-Br > C-Cl > C-S > C-O > C-N > C-C. Polyhalo compounds are completely reduced with Li and t-BuOH in THF (Winstein procedure).46 Allylic, geminal, bridgehead, and vinylic halogen atoms are removed, the latter stereospecifically. NH3 and amines have been avoided as solvents due to potential reaction with the alkyl halides by elimination or substitution.1a,47a However, Li-NH3 systems successfully reduce vinylic, bridgehead, and cyclopropyl halides47b,c and sometimes give better results than the Winstein-Gassman procedures (eq 18).47c

Alkyllithium reagents nowadays often replace Li for the preparation of organolithium compounds from alkyl or aryl bromides.48 Li has been used to couple alkyl and aryl halides in Wurtz or Wurtz-Fittig-type reactions,49 though the use of Na is much more important. Reduction of monosubstituted alkyl halides or selective reduction of geminal dihalides are best carried out with metal or complex hydrides or by catalytic hydrogenation.1b

Sulfides, sulfoxides, and sulfones are reductively cleaved with lithium.50 Reduction of sulfides in THF is improved with catalytic naphthalene. Li-EtNH2 gave better results than Sodium Amalgam for the cleavage of the C-S bond in sulfones (eq 19),51a,b and than Raney Nickel for some sulfide cleavage.51c Selenides are cleaved similarly.52 Thio- and selenoacetals are reduced to alkanes.

Allyl, benzyl, and aryl ethers are cleaved by Li in NH3 or amines.1a,b Sterically hindered steroid epoxides, which are not cleaved with LiAlH4, are converted into axial alcohols by Li-EtNH2.1b Li-ethylenediamine efficiently cleaves sterically hindered epoxides to tertiary alcohols (eq 20).53

Li promoted reductions of allyloxy and benzyloxy esters54a and esters of sterically hindered secondary and tertiary alcohols54b give rise to carboxylate cleavage, thus presenting a means of indirect deoxygenation of alcohols. Further reductive cleavages have been found with activated cyclopropanes,55 N-oxides,56 and sulfonamides.57

Li (and K) promoted reduction of TiCl3 in the McMurry reaction has been reported to be more reliable than the TiCl3/LiAlH4 reagent.58

Related Reagents.

Calcium; Lithium-Ethylamine; Potassium; Sodium; Sodium-Alcohol; Sodium-Ammonia.

1. (a) Smith, M. In Reduction: Techniques and Applications in Organic Synthesis; Augustine, R. L., Ed.; Dekker: New York, 1968; Chapter 2. (b) Hudlick&ygrave;, M. Reductions in Organic Chemistry; Horwood: Chichester, 1984. (c) Birch, A. J. QR 1950, 4, 69. (d) Benkeser, R. A. Adv. Chem. Ser. 1957, 23, 58. (e) Birch, A. J.; Smith, H. QR 1958, 12, 17. (f) Steroid Reactions; Djerassi, C., Ed.; Holden-Day: San Francisco, 1963. (g) Harvey, R. G. S 1970, 161. (h) Kaiser, E. M. S 1972, 391. (i) Birch, A. J.; Subba Rao, G. S. R. Adv. Org. Chem. 1972, 8, 1. (j) Caine, D. OR 1976, 23, 1. (k) Brendel, G. Lithium Metal in Organic Synthesis; In 3rd Lect.-Hydride Symp.; Metallges. AG: Frankfurt/Main, 1979; pp 135-155. (1) Huffman, J. W. ACR 1983, 16, 399. (m) Hook, J. M.; Mander, L. N. Nat. Prod. Rep. 1986, 3, 35. (n) Rabideau, P. W. T 1989, 45, 1579. (o) Rabideau, P. W. Marcinow, Z. OR 1992, 42, 1.
2. (a) Dye, J. L. Prog. Inorg. Chem. 1984, 32, 327. (b) Thompson, J. C. Monographs on the Physics and Chemistry of Materials: Electrons in Liquid Ammonia; Oxford University Press: Fair Lawn, NJ, 1976.
3. Gremmo, N.; Randles, J. E. B. JCS(F1) 1974, 70, 1480.
4. (a) Dewald, R. R. JPC 1975, 79, 3044. (b) Birch, A. J., Slobbe, J. H 1976, 5, 905.
5. (a) Pleskov, V. A. J. Phys. Chem. (U.S.S.R) 1937, 9, 12 (CA 1937, 31, 4214). (b) Wilds, A. L.; Nelson, N. A. JACS 1953, 75, 5360.
6. Johnson, W. C.; Piskur, M. M. JPC 1933, 37, 93.
7. For reductions with lithium bronze, see (a) Mueller, R. H.; Gillick, J. G. JOC 1978, 43, 4647. (b) Fang, J.-M. JOC 1982, 47, 3464.
8. Krapcho, A. P.; Bothner-By, A. A. JACS 1959, 81, 3658.
9. Dryden, H. L., Jr.; Webber, G. M.; Burtner, R. R.; Cella, J. A. JOC 1961, 26, 3237.
10. Evers, E. C.; Young, A. E.; II; Panson, A. J. JACS 1957, 79, 5118.
11. Dewald, R. R.; Dye, J. L. JPC 1964, 68, 128.
12. Benkeser, R. A.; Belmonte, F. G.; Kang, J. JOC 1983, 48, 2796.
13. Mander, L. N. COS 1991, 8, 489.
14. Turner, R. B.; Gänshirt, K. H.; Shaw, P. E.; Tauber, J. D. JACS 1966, 88, 1776.
15. Fried, J.; Abraham, N. A. TL 1965, 3505.
16. Fried, J.; Abraham, N. A.; Santhanakrishnan, T. S. JACS 1967, 89, 1044.
17. Camps, F.; Coll, J.; Pascual, J. JOC 1967, 32, 2563.
18. Baker, A. J.; Goudie, A. C. CC 1972, 951.
19. Sipio, W. J. TL 1985, 26, 2039.
20. Subba Rao, G. S. R.; Ramanathan, H.; Raj, K. CC 1980, 315.
21. Hamilton, R. J.; Mander, L. N.; Sethi, S. P. T 1986, 42, 2881.
22. Schultz, A. G. Sundararaman, P.; Macielag, M.; Lavieri, F. P.; Welch, M. TL 1985, 26, 4575.
23. Rabideau, P. W.; Karrick, G. L. TL 1987, 28, 2481.
24. Burgstahler, A. W.; Worden, L. R. JACS 1964, 86, 96.
25. Borowitz, I. J.; Gonis, G., Kelsey, R., Rapp, R.; Williams, G. J. JOC 1966, 31, 3032.
26. Reggel, L.; Friedel, R. A.; Wender, I. JOC 1957, 22, 891.
27. Rabideau, P. W.; Burkholder, E. G. JOC 1978, 43, 4283.
28. (a) Jaworek, W.; Vögtle, F. CB 1991, 124, 347 (CA 1991, 114, 101 319p). (b) Michel, P.; Moradpour, A. S 1988, 894.
29. (a) Koch, K.-H.; Müllen, K. CB 1991, 124, 2091. (b) Anton, U.; Göltner, C.; Müllen, K. CB 1992, 125, 2325.
30. Julina, R.; Herzig, T.; Bernet, B.; Vasella, A. HCA 1986, 69, 368.
31. Dear, R. E. A.; Pattison, F. L. M. JACS 1963, 85, 622.
32. Svoboda, M.; Závada, J.; Sicher, J. CCC 1965, 30, 413.
33. (a) Stork, G.; Malhotra, S.; Thompson, H.; Uchibayashi, M. JACS 1965, 87, 1148. (b) Miller, B. R. SC 1972, 2, 273.
34. (a) Stork, G.; Boeckmann, R. K., Jr.; Taber, D. F., Still, W. C., Singh, J. JACS 1979, 101, 7107. (b) Swartz, J. E.; Mahachi, T. J.; Kariv-Miller, E. JACS 1988, 110, 3622.
35. Huffman, J. W. COS 1991, 8, 107.
36. Huffman, J. W.; Desai, R. C.; LaPrade, J. E. JOC 1983, 48, 1474.
37. Giroud, A. M., Rassat, A. BSF 1976, 1881 (CA 1977, 87, 6251a).
38. Toromanoff, E. BSF 1987, 893 (CA 1988, 109, 128 193b).
39. (a) Stork, G.; Rosen, P.; Goldman, N.; Coombs, R. V.; Tsuji, J. JACS 1965, 87, 275. (b) Stork, G.; Logusch, E. W. JACS 1980, 102, 1218.
40. Samson, M.; De Clercq, P.; Vandewalle, M. T 1977, 33, 249.
41. (a) Burgstahler, A. W.; Sanders, M. E. S 1980, 400. (b) See also Fétizon, M.; Gore, J. TL 1966, 471.
42. Ireland, R. E.; Pfister, G. TL 1969, 2145.
43. (a) Hall, S. S.; Lipsky, S. D.; McEnroe, F. J.; Bartels, A. P. JOC 1971, 36, 2588. (b) Marcinow, Z.; Rabideau, P. W. JOC 1988, 53, 2117.
44. (a) Hall, S. S.; Lipsky, S. D. JOC 1973, 38, 1735. (b) For phenylation-reduction of aliphatic ketones see Hall, S. S.; McEnroe, F. J. JOC 1975, 40, 271.
45. Bedenbaugh, A. O.; Bedenbaugh, J. H.; Bergin, W. A.; Adkins, J. D. JACS 1970, 92, 5774.
46. (a) Bruck, P.; Thompson, D.; Winstein, S. CI(L) 1960, 405. (b) Ikan, R.; Markus, A. JCS(P1) 1972, 2423. (c) Bruck, P. TL 1962, 449. (d) For substitution of Li by Na, see: Gassman, P. G.; Pape, P. G. JOC 1964, 29, 160.
47. (a) Pinder, A. R. S 1980, 425. (b) Duggan, A. J.; Hall, S. S. JOC 1975, 40, 2238. (c) Berkowitz, D. B. S 1990, 649.
48. (a) Ziegler, K.; Colonius, H. LA 1930, 479, 135 (CA 1930, 24, 3777). (b) Jones, R. G.; Gilman, H. OR 1951, 6, 339.
49. Han, B. H.; Boudjouk, P. TL 1981, 22, 2757.
50. Caubère, P.; Coutrot, P. COS 1991, 8, 835.
51. (a) Ohmori, M.; Yamada, S.; Takayama, H. TL 1982, 23. (b) Grieco, P. A.; Masaki, Y. JOC 1974, 39, 2135. (c) Stotter, P. L.; Hornish, R. E. JACS 1973, 95, 4444. See also Truce, W. E.; Tate, D. P.; Burdge, D. N. JACS 1960, 82, 2872.
52. Sevrin, M.; Van Ende, D.; Krief, A. TL 1976, 2643.
53. Brown, H. C.; Ikegami, S.; Kawakami, J. H. JOC 1970, 35, 3243.
54. (a) Markgraf, J. H.; Hensley, W. M.; Shoer, L. I. JOC 1974, 39, 3168. (b) Boar, R. B.; Joukhadar, L.; McGhie, J. F.; Misra, S. C. CC 1978, 68.
55. Staley, S. W. Sel. Org. Transform. 1972, 2, 309.
56. White, J. D. TL 1974, 2879.
57. Cuvigny, T.; Larchevêque, M. JOM 1974, 64, 315 (CA 1974, 80, 70 494q).
58. McMurry, J. E.; Fleming, M. P.; Kees, K. L.; Krepski, L. R. JOC 1978, 43, 3255.

Karin Briner

Indiana University, Bloomington, IN, USA

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