Lithium Cyanide


[2408-36-8]  · CLiN  · Lithium Cyanide  · (MW 32.96)

(synthesis of nitriles from halides, alcohols, aldehydes, ketones; synthesis of cyanohydrins; deoxygenation of ketones)

Physical Data: mp 160 °C, d 1.025 g cm-3;1 hygroscopic solid.

Solubility: sol H2O, DMF, THF.

Form Supplied in: solid or 0.5 M solution in DMF.

Preparative Methods: from Lithium metal and Silver(I) Cyanide,2 from lithium hydride and Hydrogen Cyanide,3 or, more conveniently, from Acetone Cyanohydrin and lithium hydride.4

Handling, Storage, and Precautions: moisture-sensitive; like Sodium Cyanide and Potassium Cyanide, LiCN is highly toxic; use in a fume hood.

Nitriles (from Halides).

Nitriles can be prepared from halides (Br or I) under nonaqueous conditions using LiCN in refluxing THF for 1 h (seven examples; >90% yields).5 A simple alkyl chloride gave only a 50% yield after 18 h (one example).

Nitriles (from Alcohols).

The quantitative conversion of a tosylate to a nitrile (one example) in refluxing THF has been reported.5

Manna et al. have reported the conversion of alcohols to nitriles using LiCN under Mitsunobu conditions (Diethyl Azodicarboxylate and Triphenylphosphine; two examples, 50% yields).6

b-Hydroxynitriles (from Epoxides).

Ciaccio et al. have reported the preparation of b-hydroxynitriles from epoxides using LiCN in 60-88% yield (10 examples; eq 1).7 Cycloalkene oxides gave exclusively the trans-hydroxynitriles. Monosubstituted epoxides were reported to give exclusive attack at the less substituted carbon. Acetals, alkenes, and t-butyldimethylsilyloxy groups were shown to be stable to the reaction conditions. After an aqueous extractive workup or passage through a plug of Florisil, the crude compounds are reported to be pure by TLC, IR, and 1H and 13C NMR analysis.

Previously, in a synthesis of a dideoxynucleoside, Matsuda et al. reported the opening of an epoxide with LiCN in refluxing THF; however, LiCN in DMF gave intractable mixtures.8

Alkylsilyl Cyanides.

LiCN is reported to be the method of choice for the preparation of alkylsilyl cyanides from the corresponding chlorides.4,9 Both dialkylsilyl9 and trialkylsilyl4,9 cyanides have been reported.


Yoneda et al. have reported the preparation of trialkylsilyl cyanohydrins and acyl cyanohydrins from aldehydes and ketones.10,11 Addition of LiCN to a THF solution of the carbonyl compound and Benzoyl Chloride (nine examples),10 Acetyl Chloride (five examples),10 Chlorotrimethylsilane (six examples),10 or t-Butyldimethylchlorosilane (eight examples),11 followed by stirring at rt, results in the appropriate cyanohydrin (eq 2). Yields ranged from 47 to 100% (generally >80%; distillation or column chromatography).

Conjugate Additions.

Treatment of 4-cholesten-3-one with lithium cyanide (THF, 16 h, reflux) gives 5-cyanocholestan-3-one (80%, 5a:5b-cyano = 3:1).5


Aldehydes and ketones react rapidly with LiCN and Diethyl Phosphorocyanidate (DEPC) in THF to form cyanophosphates (eq 3).12 These cyanophosphates can serve as intermediates in the synthesis of structurally diverse nitriles. These syntheses are discussed in the appropriate sections below.

a,b-Unsaturated Nitriles.

Several procedures have appeared for the preparation of a,b-unsaturated nitriles using LiCN as a reagent (e.g. eq 4; six examples; 61-94%; column chromatography).12 A cyanophosphate when treated with Boron Trifluoride Etherate will undergo elimination to form the a,b-unsaturated nitrile. However, in the compounds examined, this elimination only occurs if R1 is an aromatic group. If R1 is an alkyl group, the cyanophosphate does not eliminate. This reaction has been used in the synthesis of lysergic acid and related compounds.13,14

A second synthesis of a,b-unsaturated nitriles, also from ketones, has been reported (eq 5).15 Reaction of a ketone to form the vinyl trifluoromethanesulfonate is followed by treatment of the triflate with LiCN, Tetrakis(triphenylphosphine)palladium(0), and 12-Crown-4 to give the a,b-unsaturated nitrile. This procedure may provide an alternative to the procedure of Harusawa, since an aromatic ketone is not required. Eight examples (all cycloalkyl ketones) were given, including one b-keto ester and two a,b-unsaturated ketones. Isolated yields (chromatography or distillation) were 59-87%.

A similar transformation on an O-triflyl imidate has been reported to occur without the need for transition metal catalysis (eq 6).16

A synthesis of a-methylenenitriles has been reported (eq 7).17 Treatment of an N-(p-tolylsulfonyl)vinylsulfoximine with LiCN in DMF for 1 h at rt gave 63-81% yields of the a-methylenenitriles (three examples).

b,g-Unsaturated Nitriles.

Aldehydes and ketones can be transformed into b,g-unsaturated nitriles.18 Treatment of the cyanophosphate derived from the carbonyl compound with Samarium(II) Iodide in THF gives the b,g-unsaturated nitrile in 60-94% yield (eq 8; column chromatography; 14 examples).

Nitriles (from Carbonyl Compounds).

Cyanophosphates can be used to prepare nitriles by treating them with either lithium in liquid ammonia (seven examples; 72-91% yields; column chromatography)19 or samarium iodide (12 examples; 61-95%; column chromatography) (eq 9).18 The Li/NH3 reduction should be carried out at -78 °C; when the reaction is done in refluxing NH3, reduction of the cyanophosphate to a methylene group can be the major product (see below).20

If one of the R groups is aromatic, then hydrogenation with a Pd catalyst will also give nitriles (two examples; 75, 81%).21

Deoxygenation of Ketones.

Cyanophosphates have also been used for the deoxygenation of a,b-unsaturated ketones and aromatic ketones (eq 10; five examples; 80-99%; no chromatography) by treatment with lithium in liquid ammonia.20 As noted above, this reaction should be carried out in refluxing NH3; at lower temperatures, reduction to the nitrile predominates. The reduction to the alkene is reported to be free of double bond isomerization or migration.

Allenic Nitriles.

Treatment of a cyanophosphate (derived from an a,b-alkynyl ketone) with a higher-order cuprate gives trisubstituted allenes (eq 11; three ketone and one aldehyde examples; five cuprate examples; 32-87%; column chromatography).22

1. (a) Wells, A. F. Structural Inorganic Chemistry, 4th ed.; Clarendon: Oxford, 1975; pp 749-751. (b) Holliday, A. K.; Hughes, G.; Walker, S. M. In Comprehensive Inorganic Chemistry; Trotman-Dickenson, A. F., Ed.; Pergamon: New York, 1973; Vol. 1, p 1245.
2. Rossmanith, K. M 1965, 96, 1690.
3. Evans, D. A.; Carroll, G. L.; Truesdale, L. K. JOC 1974, 39, 914.
4. Livinghouse, T. OSC 1990, 7, 517.
5. Harusawa, S.; Yoneda, R.; Omori, Y.; Kurihara, T. TL 1987, 28, 4189.
6. Manna, S.; Falck, J. R.; Mioskowski, C. SC 1985, 15, 663.
7. Ciaccio, J. A.; Stanescu, C.; Bontemps, J. TL 1992, 33, 1431.
8. Matsuda, A.; Satoh, M.; Nakashima, H.; Yamamoto, N.; Ueda, T. H 1988, 27, 2545.
9. Mai, K.; Patil, G. JOC 1986, 51, 3545.
10. Yoneda, R.; Santo, K.; Harusawa, S.; Kurihara, T. S 1986, 1054.
11. Yoneda, R.; Hisakawa, H.; Harusawa, S.; Kurihara, T. CPB 1987, 35, 3850.
12. Harusawa, S.; Yoneda, R.; Kurihara, T.; Hamada, Y.; Shioiri, T. TL 1984, 25, 427.
13. Yoneda, R.; Terada, T.; Harusawa, S.; Kurihara, T. H 1985, 23, 557.
14. Kurihara, T.; Terada, T.; Harusawa, S.; Yoneda, R. CPB 1987, 35, 4793.
15. Piers, E.; Fleming, F. F. CC 1989, 756.
16. Sisti, N. J.; Fowler, F. W.; Grierson, D. S. SL 1991, 816.
17. Bailey, P. L.; Jackson, R. F. W. TL 1991, 32, 3119.
18. Yoneda, R.; Harusawa, S.; Kurihara, T. JOC 1991, 56, 1827.
19. Yoneda, R.; Osaki, T.; Harusawa, S.; Kurihara, T. JCS(P1) 1990, 607.
20. Yoneda, R.; Osaki, H.; Harusawa, S.; Kurihara, T. CPB 1989, 37, 2817.
21. Harusawa, S.; Nakamura, S.; Yagi, S.; Kurihara, T.; Hamada, Y.; Shioiri, T. SC 1984, 14, 1365.
22. Yoneda, R.; Inagaki, N.; Harusawa, S.; Kurihara, T. CPB 1992, 40, 21.

Ronald H. Erickson

Scios Nova, Baltimore, MD, USA

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