Lithium-Ethylamine1

Li-EtNH2
(Li)

[7439-93-2]  · Li  · Lithium-Ethylamine  · (MW 6.94) (EtNH2)

[75-04-7]  · C2H7N  · Lithium-Ethylamine  · (MW 45.10)

(powerful reducing agent;1 used for (partial) reduction of aromatics;1a-d,f conversion of alkynes to trans-alkenes and alkanes;1a,f stereoselective reduction of hindered ketones1a,e,13b and oximes;16 reductive cleavage of polar single bonds1a,b,d,f,19,27a)

Physical Data: Li: mp 180.5 °C; bp 1327 ± 10 °C; d 0.534 g cm-3. EtNH2: mp -81 °C; bp 16.6 °C; d 0.689 g cm-3.

Form Supplied in: see Lithium; ethylamine, 99% anhydrous, packaged in steel cylinders fitted with stainless steel valves.

Purification: see Lithium; ethylamine can be purified by distillation from sodium under exclusion of H2O and CO2.

Handling, Storage, and Precautions: see Lithium. Ethylamine is a toxic, colorless, and highly flammable gas with a low flash point (-16 °C). It should be handled in a well-ventilated hood, only after having eliminated all potential sources of ignition. It is corrosive to Cu, Al, Sn, Zn, and their alloys, but is stored satisfactorily in stainless steel.

Lithium-Ethylamine Solutions.

Lithium dissolves in EtNH2 to give deep-blue solutions due to solvated electrons.2a-d Similar solutions are obtained with Li in other primary amines.2a,b EtNH2 and ethylenediamine (EDA) are the most common solvents, but methylamine, propylamine, isopropylamine, and butylamine have also been used for reductions. The other alkali metals are less soluble in these amines and rarely used for reductions in amines. For instance, the solubilities in EDA at room temperature are 2.9 × 10-1 mol L-1 (Li), 2.4 × 10-3 (Na), 1.0 × 10-2 (K), 1.3 × 10-2 (Rb), and 5.4 × 10-2 (Cs).2e However, the solubilities can dramatically be increased by using crown ether and cryptand complexants.2a,b In contrast to the Li-amine solutions, the amine solutions of K, Rb, and Cs contain, besides solvated electrons, the metal anion as major species, while Na-amine solutions contain only the metal anion and are in general not blue at all.2a,b More recently, methylamine-assisted solubilization of Li and Li-Na mixtures (up to 1:1) in several amine and ether solvents, in which the metals alone are not or only slightly soluble, has been reported.3

The reducing agents formed by Li in amines (Benkeser reduction) are more powerful but less selective than Li in NH3.1a,4 The higher reactivity is caused by higher reaction temperatures and possibly also by a smaller degree of electron solvation; the better solubility of many organic compounds in amines is also advantageous. The reactivity can be modified by using lower reaction temperatures and by addition of alcohols and secondary amines. Li-amine solutions are more sensitive to catalytic decomposition than Li in NH3,5 and clean solvents are mandatory.

Experimental.

Detailed procedures are available,1b,c as are details for reaction assemblies.6 Reduction occurs by a sequence of single electron and proton transfers to the substrate, resulting in saturation of multiple bonds or fission of single bonds (see also Lithium).

Reduction of Aromatic Compounds.

Li-EtNH2 reduces benzene and its derivatives to cyclohexenes.1a-d Monoalkylbenzenes give mixtures of regioisomers. More selective formation of the D1-ene is achieved when the reaction is performed in a mixture of primary and secondary amines.1a With excess Li and at higher temperatures, further reduction to cyclohexanes can occur (eq 1).4

Li-EtNH2 affords, in the presence of alcohols (alcohol:-Li > 1:1), Birch reduction products, i.e. 1,4-cyclohexadienes.1a,d This procedure is more powerful than the Birch method (eq 2) and useful for the reduction of highly substituted benzene rings.7 Li-EDA reductions of benzene derivatives have been performed (eq 2),7b,8a,b but Li-EtNH2 appears to be superior for cyclohexene formation, probably due to the presence of N-lithioethylenediamine in refluxing EDA.7b Cyclohexenes and cyclohexa-1,4-dienes are formed in high yields by electrolysis of benzene derivatives with LiCl in MeNH2 in a divided or undivided cell, respectively.1a

Reduction of polycyclic aromatic compounds is complex, and the products delicately depend on the exact reaction conditions. Most extensive reductions have been achieved with Li-EDA.1f Ferrocenes have been reductively cleaved with Li-propylamine in 35-77% yield.9

Alkenes.

Terminal10a-c and internal double bonds may be reduced by Li-amine; however, the latter react more slowly.1a,b,d Strained cyclic alkenes are more easily reduced, and ring size effects are observed. Na-t-BuOH-HMPA is more powerful and reduces even nonterminal alkenes in nearly quantitative yields.10d

Alkynes.

Internal alkynes are rapidly reduced to trans-alkenes by stoichiometric amounts of Li in amines.1a Excess Li leads to alkanes.11 Ca in MeNH2/EDA (1:1) has been used for similar reductions.12 Li-EtNH2-t-BuOH efficiently reduced an alkyne precursor of sphingosin, while triple bond reduction was incomplete with Na- and Li-NH3.6b For the conversion of 1-alkynes to 1-alkenes, Na-NH3-(NH4)2SO4 is the system of choice.1a Li-EDA reduction of 1-alkynes usually gives alkanes.

Ketones.

Steroidal and triterpenoid ketones have been selectively reduced to the equatorial alcohols by Li-EDA in high yields.10b,13 Stereoselective reduction of an a,b-unsaturated ketone to the (20R)(b)-alcohol was achieved with Li-EDA, while Sodium Borohydride led to a mixture of the (20R)(b)-alcohol and the D16-(20S)-alcohol (eq 3).14 Li-EtND2-t-BuOD reduces a,b-unsaturated ketones to the saturated ketones in high yields and deuteriates the b-C-atom stereoselectively.15 Li-EtNH2 reduction of 3-oximino steroids is apparently the best procedure to prepare 3b-amino steroids.16

Carboxylic Acids and Derivatives.

Li-MeNH2 or -EtNH2 reduce aliphatic saturated acids to aldehydes or imines in 53-84% yield, depending on the workup procedure.17 Tertiary carboxamides are cleaved to aldehydes.18 A major limitation is the substantial formation of transamidation byproducts. N-Proline peptide bonds have been cleaved to an extent of 50-70 %.18a

Reductive Cleavage of C-S and C-Se Bonds.19

Mainly sulfones,20 but also sulfoxides,21 sulfides,22 and dithioacetals23 have been desulfurized by Li in amines, most often in EtNH2, but also in EDA20g,h and MeNH2.20f As an excess of reducing agent is normally used, functional groups sensitive to SET may be reduced. Li-EtNH2 cleaves allylic C-S bonds generally without side-reactions and has thus proven to be especially useful in terpene synthesis for the reductive removal of sulfur-containing functional groups.20a-c,22a,b

Allylic aryl sulfones were converted to the alkenes by Li-EtNH2 in 77-98 % yield,20a-c while Sodium Amalgam caused double bond migration (eq 4)20a or (E)/(Z) isomerization.20b However, in some cases, extensive double bond migration using Li-EtNH2 or Li-EDA has been observed.20d

Vinyl sulfones have been hydrogenolyzed to 2-alkenes by Li-EtNH2 or C8K in Et2O with extensive isomerization of the cis double bond, forming cis/trans mixtures, while Aluminum Amalgam gave no reduction at all.20e Besides arylsulfonyl groups, some alkylsulfonyl groups have also been reductively removed by Li-EtNH2 or -MeNH2.20c,f Allylic alcohols survived the reductive cleavage of a sulfoxyl group by Li-EtNH2 at -78 °C, whereas the double bond was simultaneously reduced when Raney Nickel was used.21 While unsatisfactory results were obtained from attempts to desulfurize a 4-thiacyclohexene with Raney Ni, stepwise reduction using Li-EtNH2, followed by Raney Ni to reduce the intermediate Li thiolate, yielded the alkene in 55-70%.22c Li-EtNH2 reductively cleaves allylic N,N-dimethyldithiocarbamates that have been employed in the synthesis of disubstituted alkenes, in 90-95% yield.24 Selenides and diselenoacetals are reduced to the corresponding alkanes by Li-EtNH2 or Raney Ni in good yields.25

Epoxides.

Sterically hindered steroid and triterpenoid epoxides are reductively opened to the axial alcohols by Li-EtNH226a and Li-EDA.26b Thus Li-EDA reduced 3a,4a-epoxyfriedelan to the 4a-alcohol (eq 5), while Lithium Aluminum Hydride did not give any reduction at all, and the 3b,4b-isomer to the 3b-alcohol (eq 6).26b Reductive opening of other tri- and tetrasubstituted epoxides with Li-EtNH226c-e and Li-EDA26f are high yielding, but depending on the substrate, mixtures of alcohols are encountered.26d-g Reductions with Li in propylamine and butylamine seem to give more side-products.26e

Li-EDA27a,b and Ca-EDA27a are excellent reductants for epoxides of bicyclic compounds which react sluggishly and often undergo rearrangements with LiAlH4 (eq 7)27b Lithium Triethylborohydride has proven to be a powerful reductant for bicyclic and tri- and tetrasubstituted oxiranes and is in some instances superior to Li-EDA.27c

Reductive Cleavage of Miscellaneous Single Bonds.

Allyl and benzyl ethers are cleaved by Li-MeNH2 or -EtNH2 in fair to good yields28 (eqs 8 and 928d,e).

Similarly, the reductive cleavage of the O-alkyl bonds of esters of allylic alcohols is effected by Li-EtNH2;28e allylic alcohols are normally not efficiently cleaved unless they are sterically hindered (eq 9).28e

Esters of tertiary and sterically hindered secondary alcohols are cleaved to the corresponding alkanes and carboxylates by Li-EtNH229a and Li-EDA,29b, whereas the parent alcohol is regenerated from nonhindered esters. This allows the selective deoxygenation of suitable diesters (eq 10).29a

Esters of moderately hindered secondary alcohols often give mixtures of alkane and alcohol. Using Potassium 18-Crown-6 in t-Butylamine, the alkane:alcohol ratio seems to be somewhat higher.29a Sodium-Hexamethylphosphoric Triamide-t-butanol is another efficient system for the transformation of hindered esters to alkanes.29c K-Na eutectic solubilized with 18-crown-6 in t-butylamine and THF deoxygenates hindered and nonhindered esters.29a Alcohol regeneration by Li in refluxing EtNH2 seems to be essentially due to transacylation, leading to N-ethylamides, while at low temperature the Bouveault-Blanc reaction predominates.29a Methyl esters of bulky carboxylic acids have been converted to the acids by Li in refluxing EDA.29d

Phosphorodiamidates are cleaved to alkanes by Li-EtNH2, providing another indirect method for the deoxygenation of alcohols (eq 11).30

Li-amine reagents have been used for the cleavage of vinyl phosphates to alkenes,31 of oxetanes,32 of bicyclobutanes,33 and of allylic N,N-diacylhydrazines.34 Li-EDA cleaves glycosyluronic acid-containing oligosaccharides specifically at the site of the acid residue.35

Related Reagents.

Lithium; Potassium; Sodium; Sodium-Ammonia.


1. (a) Kaiser, E. M. S 1972, 391. (b) Smith, M. In Reduction: Techniques and Applications in Organic Synthesis; Augustine, R. L.; Ed.; Dekker: New York, 1968; Chapter 2. (c) Birch, A. J.; Subba Rao, G. Adv. Org. Chem. 1972, 8, 1. (d) Brendel, G. Lect.-Hydride Symp., 3rd: Lithium Metal in Organic Synthesis; Metallges. AG: Frankfurt/Main, 1979; pp 135-55. (e) Steroid Reactions; Djerassi, C., Ed.; Holden-Day: San Francisco, 1963. (f) Hudlický, M. Reductions in Organic Chemistry; Horwood: Chichester, 1984.
2. (a) Dye, J. L. Prog. Inorg. Chem. 1984, 32, 327. (b) Dye, J. L. AG(E) 1979, 587. (c) Catterall, R.; Hurley, I.; Symons, M. C. R. JCS(D) 1972, 139. (d) Bar-Eli, K.; Tuttle, T. R., Jr. JCP 1964, 40, 2508. (e) Dewald, R. R.; Dye, J. L. JPC 1964, 68, 121 & 128.
3. Faber, M. K.; Fussá-Rydel, O.; Skowyra, J. B.; McMills, L. E. H.; Dye, J. L. JACS 1989, 111, 5957.
4. Benkeser, R. A.; Robinson, R. E.; Sauve, D. M.; Thomas, O. H. JACS 1955, 77, 3230.
5. Evers, E. C.; Young, A. E., II; Panson, A. J. JACS 1957, 79, 5118.
6. (a) FF 1967, 1, 580. (b) Julina, R.; Herzig, T.; Bernet, B.; Vasella, A. HCA 1986, 69, 368.
7. (a) Burgstahler, A. W.; Worden, L. R. JACS 1964, 86, 96. (b) Kwart, H.; Conley, R. A. JOC 1973, 38, 2011. (c) Harvey, R. G.; Urberg, K. JOC 1968, 33, 2206.
8. (a) Krapcho, A. P.; Bothner-By, A. A. JACS 1959, 81, 3658. (b) Stolow, R. D.; Ward, R. A. JOC 1966, 31, 965.
9. Brown, A. D., Jr.; Reich, H. JOC 1970, 35, 1191.
10. (a) Ficini, J.; Francillette, J.; Touzin, A. M. JCR(M) 1979, 35, 1820 (CA 1980, 92, 93 777w). (b) Pradhan, B. P.; Chakrabarti, D. K.; Chakraborty, S. IJC(B) 1984, 23B, 1115. (c) Corey, E. J.; Cantrall, E. W. JACS 1959, 81, 1745. (d) Whitesides, G. M.; Ehmann, W. J. JOC 1970, 35, 3565.
11. Benkeser, R. A.; Schroll, G.; Sauve, D. M. JACS 1955, 77, 3378.
12. Benkeser, R. A.; Belmonte, F. G. JOC 1984, 49, 1662.
13. (a) Sengupta, P.; Das, S.; Das, K. IJC(B) 1984, 23B, 1113. (b) Huffman, J. W. COS 1991, 8, 107.
14. Sengupta, P.; Sen, M.; Sarkar, A.; Das, S. IJC(B) 1986, 25B, 975. see also Markgraf, J. H.; Davis, H. A.; Mahon, B. R. J. Chem. Educ. 1988, 65, 635.
15. Burgstahler, A. W.; Sanders, M. E. S 1980, 400.
16. Khuong-Huu, F.; Tassel, M. BSF 1971, 4072 (CA 1972, 76, 86 004h).
17. Bedenbaugh, A. O.; Bedenbaugh, J. H.; Bergin, W. A.; Adkins, J. D. JACS 1970, 92, 5774.
18. (a) Patchornik, A.; Wilchek, M.; Sarid, S. JACS 1964, 86, 1457. (b) Bedenbaugh, A. O.; Payton, A. L.; Bedenbaugh, J. H. JOC 1979, 44, 4703.
19. Caubère, P.; Coutrot, P. COS 1991, 8, 835.
20. (a) Grieco, P. A.; Masaki, Y. JOC 1974, 39, 2135. (b) Ohmori, M.; Yamada, S.; Takayama, H. TL 1982, 23, 4709. (c) Trost, B. M.; Weber, L.; Strege, P.; Fullerton, T. J.; Dietsche, T. J. JACS 1978, 100, 3426. (d) Julia, M.; Uguen, D. BSF 1976, 513 (CA 1976, 85, 63 175m). (e) Savoia, D; Trombini, C.; Umani-Ronchi, A. JCS(P1) 1977, 123. (f) Truce, W. E.; Tate, D. P.; Burdge, D. N. JACS 1960, 82, 2872. (g) Bödeker, C.; de Waard, E. R.; Huisman, H. O. T 1981, 37, 1233. (h) Fehr, C. HCA 1983, 66, 2512.
21. Solladie, G.; Demailly, G; Greck, C. JOC 1985, 50, 1552.
22. (a) Biellmann, J. F.; Ducep, J. B. T 1971, 27, 5861 (CA 1972, 76, 34 427d). (b) van Tamelen, E. E.; McCurry, P.; Huber, U. PNA 1971, 68, 1294. (c) Stotter, P. L.; Hornish, R. E. JACS 1973, 95, 4444.
23. Crossley, N. S.; Henbest, H. B. JCS 1960, 4413.
24. Hayashi, T.; Midorikaw, H. S 1975, 100.
25. Sevrin, M.; Van Ende, D.; Krief, A. TL 1976, 2643.
26. (a) Hallsworth, A. S.; Henbest, H. B. JCS 1957, 4604 & 1960, 3571. (b) Sengupta, P.; Das, K.; Das, S. IJC(B) 1985, 24B, 1175. (c) Sedzik-Hibner, D.; Chabudzinski, Z. Rocz. Chem. 1970, 44, 2387 (CA 1971, 75, 20 641m). (d) Chabudzinski, Z.; Sedzik, D.; Szykula, J. Rocz. Chem. 1967, 41, 1923 (CA 1968, 68, 87 403j). (e) Chabudzinski, Z.; Sedzik, D.; Rykowski, Z. Rocz. Chem. 1967, 41, 1751 (CA 1968, 68, 78 435u). (f) Gurudutt, K. N.; Rao, S.; Shaw, A. K. IJC(B) 1991, 30B, 345.
27. (a) Murai, S. COS 1991, 8, 871. (b) Brown, H. C.; Ikegami, S.; Kawakami, J. H. JOC 1970, 35, 3243. (c) Krishnamurthy, S; Schubert, R. M.; Brown, H. C. JACS 1973, 95, 8486.
28. (a) Kobayashi, T.; Tsuruta, H. S 1980, 492. (b) Dasgupta, S. K.; Crump, D. R.; Gut, M. JOC 1974, 39, 1658. (c) Masamune, T.; Matsue, H.; Fujii, M. BCJ 1972, 45, 1812. (d) Rigby, J. H. TL 1982, 23, 1863. (e) Hallsworth, A. S.; Henbest, H. B.; Wrigley, T. I. JCS 1957, 1969.
29. (a) Barrett, A. G. M.; Godfrey, C. R. A.; Hollinshead, D. M.; Prokopiou, P. A.; Barton, D. H. R.; Boar, R. B.; Joukhadar, L.; McGhie, J. F.; Misra, S. C. JCS(P1) 1981, 1501. (b) Sengupta, P.; Sen, M.; Das, S. IJC(B) 1979, 18B, 179. See also: Pradhan, B. P.; Hassan, A.; Shoolery, J. N. TL 1984, 25, 865. (c) Deshayes, H.; Pete, J.-P. CJC 1984, 62, 2063 (CA 1985, 102, 24 920a). (d) Sengupta, P.; Sen, M.; Das, S. IJC(B) 1980, 19B, 721.
30. (a) Ireland, R. E.; Muchmore, D. C.; Hengartner, U. JACS 1972, 94, 5098. (b) Liu, H. J.; Lee, S. P. TL 1977, 3699.
31. Ireland, R. E.; Pfister, G. TL 1969, 2145.
32. Sauers, R. R.; Schinski, W.; Mason, M. M.; O'Hara, E; Byrne, B. JOC 1973, 38, 642.
33. Moore, W. R.; Hall, S. S.; Largman, C. TL 1969, 4353.
34. (a) Anastasia, M.; Fiecchi, A.; Galli, G. JOC 1981, 46, 3421. (b) Anastasia, M.; Ciuffreda, P.; Fiecchi, A. CC 1982, 1169.
35. Lau, J. M.; McNeil, M.; Darvill, A. G.; Albersheim, P. Carbohydr. Res. 1987, 168, 219 & 245.

Karin Briner

Indiana University, Bloomington, IN, USA



Copyright 1995-2000 by John Wiley & Sons, Ltd. All rights reserved.