Lithium Amide1

LiNH2

[7782-89-0]  · H2LiN  · Lithium Amide  · (MW 22.97)

(strong base; used in N-alkylation of aromatic amines,5,6 Claisen condensations,7 a-alkylations of carbonyl compounds,13 eliminations21 and isomerizations,26 synthesis of ethynyl compounds16 and alkynyl carbinols30)

Physical Data: mp 380-400 °C; d 1.178 g cm-3.

Solubility: sl sol liq NH3, ethanol; insol ether, benzene, toluene.

Form Supplied in: gray-white powder; widely available.

Analysis of Reagent Purity: several titration procedures are available.2

Preparative Method: in a typical procedure3 for the preparation of lithium amide in ammonia, a small piece of Lithium metal is added to commercial anhyd liquid NH3 with stirring; after the almost immediate appearance of a blue color, a few crystals of iron(III) nitrate are added, followed by small portions of lithium metal; after about 20 min the blue color disappears and a gray suspension of lithium amide is formed.

Handling, Storage, and Precautions: the dry solid is flammable, air- and moisture-sensitive, and must be stored in tightly stoppered bottles; in water, it decomposes slowly when in lumps, faster in smaller particle sizes; like other alkali metal amides, the reagent must be guarded against air oxidation to prevent the formation of potentially explosive substances;4 samples which develop a yellow or green or darker color should be properly disposed of; if left open for minimal periods during weighing, the titer remains fairly constant; contact with skin causes burns; use in a fume hood.

N-Alkylation of Amines.

Lithium amide has been employed as a powerful base in the N-alkylation of heterocyclic aromatic amines.5 A variety of N-substituted 2-aminopyridines, 2-aminopyrimidines, and 2-aminolepidines have been prepared by treating the respective amine with 2 equiv LiNH2 and the alkyl halide (eq 1).6 Lithium amide is more easily handled than Sodium Amide and is therefore the reagent of choice in these reactions.

Condensations of Esters with Carbonyl Compounds.

Hauser and Puterbaugh found LiNH2 superior to sodium amide in condensations of t-butyl acetate with ketones (eq 2).7 Condensations with acetophenone, p-nitrocaprophenone, benzaldehyde, acetone, and cyclohexanone proceeded in good yields (53-76%).

This condensation method is a useful alternative to the Reformatsky reaction, and in certain cases compares favorably in terms of yields and practicality. Later studies simulated a Reformatsky-type reaction employing t-butyl acetate instead of an a-halo ester.8 It was found that this type of aldol condensation may be effected more conveniently and in higher yields by means of LiNH2, and that the use of Zinc Chloride was unnecessary in this case. Use of NaNH2 under similar conditions failed to give b-hydroxy esters. Hauser and Lindsay further reported9 that when ethyl acetate was employed instead of t-butyl acetate, self-condensation of the ester could be circumvented by using 2 equiv LiNH2. Under these conditions, even benzophenone could be condensed with ethyl acetate. It is suggested that the extra equivalent of LiNH2 coordinates with the monolithio salt of ethyl acetate, as in (1), or in a dimer or trimer. Some sort of coordination is indicated, since an extra equivalent of LiNH2 retards the self-condensation of EtOAc; NaNH2, which should coordinate to a smaller degree, fails to exhibit such a retarding effect under similar conditions.3,10

Ethyl 3-alkoxy-2-butenoates have been condensed with aldehydes in the presence of LiNH2 at the g-position to give dihydropyrones which, under the basic conditions employed, give rise to 3-alkoxy-cis-2-trans-4-unsaturated acids (eq 3).11

Along similar lines, enol silyl ethers are alkylated in high yields with lithium amide and alkyl halides.12 When alkylation of (2) is attempted with Methyllithium and 3-bromopropionitrile, E2 elimination predominates, yielding polyacrylonitrile and cyclohexanone; the same reaction using LiNH2 instead results in a 48% yield of the alkylated product (eq 4).

Alkylation of t-Butyl Esters with Organic Halides.

The direct alkylation of t-butyl acetate is a valuable alternative to the malonic ester method for preparing mono- and dibasic carboxylic acids. Monoalkylation is observed with various alkyl or alkenyl halides in very good yields using LiNH2 (eqs 5 and 6);13 in contrast, NaNH2 gives rise to dialkylated products under the same conditions. t-Butyl propionate and n-butyrate have also been alkylated in excellent yields using LiNH2. With 1,4-dibromobutane, suberic acid was obtained in quantitative yield after saponification. 1,2-Dibromoethane gave succinic acid in moderate yield, whereas use of NaNH2 in the latter case did not provide any product.

Treatment of t-butyl acetate with LiNH2 and 1,4-dibromo-2-butene gave the diester of 4-octenedioic acid (eq 7). a,b-Unsaturated esters furnished a-mono- and a,a-dialkylation products with LiNH2 (eq 8); no g-alkylated products were formed in these reactions.14

Alkylation and Condensation of Substituted Succinic Acid Derivatives.

Both monoester isomers of 2-alkyl- or arylsuccinic acids were alkylated exclusively on the carbon adjacent to the ester function (see 3) using 2 equiv LiNH2.15 In contrast, the anion obtained from diethyl 2-methylsuccinate gave on methylation a mixture of alkylated esters, including the diesters of 2,2-dimethylsuccinic and 2,3-dimethylsuccinic acids.

Condensation of monoester dianions with ketones or benzaldehyde similarly took place at the carbon a to the ester group, but only when the methylene group was not substituted (i.e. 4). Condensation products were not obtained from the isomer (3).

Reactions with Alkyne Derivatives.

Alkynes carrying functional groups such as NHR or OH can be alkylated in high yields in the presence of lithium amide (eqs 9 and 10).16-20 1-Alkyn-o-ols are alkylated by primary or secondary alkyl halides in 50-80% yields, and it is not necessary to protect the alcohols.

Eliminations and Isomerizations.

LiNH2 has been found superior to sodium amide in dehydrohalogenations of g-methallyl chloride and a-methallyl chloride to give 3-methylcyclopropene and 1-methylcyclopropene, respectively (eqs 11 and 12).21-23 Potassium Amide, on the other hand, isomerizes the a-isomer to methylenecyclopropane.24

In the dimerization of cyclopropene in the presence of alkali amides (eq 13), two opposing factors influence the course of the reaction.25 On the one hand, the rate of cyclopropenylcyclopropane formation is retarded in the presence of stronger base (KNH2) due to lower concentrations of unmetalated cyclopropene. On the other hand, increasing base strength favors the equilibrium between (6) and (7) in favor of (7), thus securing a greater yield of bicyclopropylidene (8). The best yields of (8) were obtained using LiNH2 in liquid NH3, albeit with much longer reaction times (4 weeks at -50 °C) than with NaNH2.

The propargyl sulfides (9) and (10) have been isomerized in good yields to the corresponding allenes with LiNH2 in liquid NH3 (eqs 14 and 15).26-28

Chiral propargyl alcohols can be prepared29 from allylic alcohols by Sharpless asymmetric epoxidation,30 conversion of the alcohol product into the corresponding chloride, and treatment with LiNH2 in liquid NH3 (eq 16). Use of Lithium Diisopropylamide (LDA) gives comparable yields. The same reaction with n-Butyllithium in THF at -33 °C results in mixtures of the chlorovinyl alcohol, propargyl alcohol, and starting material. It appears that n-BuLi reacts indiscriminately with both the epoxy chloride and the chlorovinyl alcohol formed during the reaction.

2-Chloromethyltetrahydrofuran undergoes ring opening followed by dehydrochlorination with 3 equiv of LiNH2.31 The lithio acetylide (11) formed in situ can be alkylated to give 4-alkynyl alcohols (eq 17).

This reaction has been employed in the synthesis of chiral alkynyl compounds from simple carbohydrate precursors (eq 18).32 The elimination reaction here is chemoselective, since the other isopropylidene group in the substrate remains unaffected.

Related Reagents.

Lithium Diethylamide; Lithium Diisopropylamide; Lithium Hexamethyldisilazide; Lithium Piperidide; Lithium Pyrrolidide; Lithium 2,2,6,6-Tetramethylpiperidide; Potassium Amide; Sodium Amide.


1. (a) Bergstrom, F. W.; Fernelius, W. C. CRV 1933, 12, 43; (b) Bergstrom, F. W.; Fernelius, W. C. CRV 1937, 20, 413.
2. See references cited in: Duhamel, L.; Plaquevent, J.-C. JOM 1993, 448, 1.
3. Dunnavant, W. R.; Hauser, C. R. JOC 1960, 25, 503.
4. Leffler, M. T. OR 1942, 1, 91.
5. Kaye, I. A. JACS 1949, 71, 2322.
6. Kaye, I. A.; Kogon, I. C. JACS 1951, 73, 5891.
7. Hauser, C. R.; Puterbaugh, W. H. JACS 1953, 75, 1068.
8. Hauser, C. R.; Puterbaugh, W. H. JACS 1951, 73, 2972.
9. Hauser, C. R.; Lindsay, J. K. JACS 1955, 77, 1050.
10. (a) Dunnavant, W. R.; Hauser, C. R. OS 1964, 44, 56. (b) Dunnavant, W. R.; Hauser, C. R. OSC 1973, 5, 564.
11. Smissman, E. E.; Voldeng, A. N. JOC 1964, 29, 3161.
12. (a) Binkley, E. S.; Heathcock, C. H. JOC 1975, 40, 2156. (b) Patterson, J. W., Jr.; Fried, J. H. JOC 1974, 39, 2506.
13. Sisido, K.; Kazama, Y.; Kodama, H.; Nozaki, H. JACS 1959, 81, 5817.
14. Sisido, K.; Sei, K.; Nozaki, H. JOC 1962, 27, 2681.
15. Kofron, W. G.; Wideman, L. G. JOC 1972, 37, 555.
16. Flahaut, J.; Miginiac, P. HCA 1978, 61, 2275.
17. Rao, A. V. R.; Reddy, E. R. TL 1986, 27, 2279.
18. Rao, A. V. R.; Reddy, E. R.; Sharma, G. V. M.; Yadagiri, P.; Yadav, J. S. TL 1985, 26, 465.
19. Claesson, A.; Olsson, L. I.; Sullivan, G. R.; Mosher, H. S. JACS 1975, 97, 2919.
20. (a) Landor, S. R.; Punja, N. TL 1966, 4905. (b) Cowie, J. S.; Landor, P. D.; Landor, S. R.; Punja, N. JCS(P1) 1972, 2197.
21. Wawzonek, S.; Studnicka, B. J.; Zigman, A. R. JOC 1969, 34, 1316.
22. (a) Köster, R.; Arora, S.; Binger, P. AG(E) 1970, 9, 810; (b) Köster, R.; Arora, S.; Binger, P. LA 1973, 1219.
23. Fisher, F.; Applequist, D. E. JOC 1965, 30, 2089.
24. Le Perchec, P.; Conia, J. M. TL 1970, 1587.
25. (a) Schipperijn, A. J. RTC 1971, 90, 1110. (b) Schipperijn, A. J.; Smael, P. RTC 1973, 92, 1121.
26. Schuijl, P. J. W.; Brandsma, L. RTC 1969, 88, 1201.
27. Meijer, J.; Brandsma, L. RTC 1972, 91, 578.
28. Brandsma, L.; Jonker, C.; Berg, M. H. RTC 1965, 84, 560.
29. Yadav, J. S.; Deshpande, P. K.; Sharma, G. V. M. T 1990, 46, 7033.
30. Katsuki, T.; Sharpless, K. B. JACS 1980, 102, 5974.
31. Ohloff, G.; Vial, C.; Näf, F.; Pawlak, M. HCA 1977, 60, 1161.
32. (a) Yadav, J. S.; Chander, M. C.; Rao, C. S. TL 1989, 30, 5455. (b) Yadav, J. S.; Krishna, P. R.; Gurjar, M. K. T 1989, 45, 6263.

Ihsan Erden

San Francisco State University, CA, USA



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