Lithium Dicyclohexylamide

[4111-55-1]  · C12H22LiN  · Lithium Dicyclohexylamide  · (MW 187.29)

(performs as a strong base, allowing deprotonation of ketones,1 esters,2 aryl3 and allyl4,5 halides, alkyl dihalides,6 allenes,7 alkylboron reagents,8 azulene and methylazulenes;9 used for the formation of formamides, glyoxylamides, oxomalonamides, and tartronamides10)

Physical Data: IR (solution/suspension in benzene, 3000-2400 cm-1): 2916s, 2880s, 2850s, 2831s, 2757m, 2620w, 2572w; 635s and 270s also reported.11

Solubility: partially sol benzene, hexanes; sol THF.

Preparative Methods: from the reaction of dicyclohexylamine with n-Butyllithium in hexanes and benzene at 0 °C; solvent can then be removed under reduced pressure and the resulting free flowing solid dissolved in THF.12

Handling, Storage, and Precautions: both solution and solid are pyrophoric and air- and moisture-sensitive; also the solid is spontaneously flammable in air. The reagent is corrosive and extremely destructive to tissues of the mucous membranes and the upper respiratory tract, eyes, and skin. Note that dicyclohexylamine is a suspected carcinogen and may cause chemical pneumonitis and pulmonary edema.13 Use in a fume hood.

Introduction.

The title reagent (Cy2NLi) has generally been used as a base in the formation of organolithium substrates in a similar way to Lithium Diisopropylamide and related lithium amides. It is reported, however, to be a stronger base than LDA, Lithium Diethylamide, and lithium isopropylcyclohexylamide (LiN(i-Pr)Cy).14 Also the conjugate acid (Cy2NH) has been shown to be a weaker acid than diisopropylamine, isopropylcyclohexylamine, and diethylamine.14

As a general note, a number of different methods for the removal of the dicyclohexylamine byproduct have been developed because of the formation of a precipitate with HCl workups. Use of HCl will cause the formation of a precipitate, which has been removed by filtration and the filtrate then subjected to standard workup.9 Citric acid1,3 and ammonium chloride4 have been used without any problems of precipitation (the former used specifically to prevent this problem). In one case, the amine has been removed by distillation. Both MeI and BF3.Et2O have been used to precipitate the amine followed by filtration and subsequent standard workup of the filtrate.5

Deprotonation of Carbonyl Compounds.

In the formation of b-keto esters from unsaturated ketones, Cy2NLi was found to give better results than the other bases examined (LDA, Sodium Hydride, Potassium t-Butoxide) (eqs 1 and 2).1 It was reported that Cy2NLi overcomes the problems of substrate self-condensation side-products and nucleophilic attack of base on diethyl carbonate. It has also been used in condensation reactions between ethyl 2-(trimethylsilyl)acetate and a number of ketones (eq 3).2

Deprotonation of Allenes.

Normally the deprotonation of alkoxyallenes leads to a-lithiation;15 however, in conjunction with bulky alkoxy groups on alkoxyallenes, the steric size of Cy2NLi has been used to give selective g-deprotonation of alkoxyallenes (eq 4).7

Deprotonation of Alkyl Halides.

In studies of the deprotonation of mono- and dihaloalkyl and -aryl compounds, the choice of base has been found to be crucial for the deprotonation of substrates that contain sites more reactive towards nucleophilic attack (eq 5).6 In one example, the dihalomethylhydroxy product of the condensation of dihalolithiomethane with a carbonyl has been used to obtain the ring expanded ketone (eq 6).16

For the formation of carbenes via deprotonation of aryl halides (eq 7), a number of bases have been investigated including Cy2NLi.3 These studies also looked at the formation of benzyne intermediates from o-chloroanisole (eq 8).

While Cy2NLi was found to give consistently better results than LDA, LiN(i-Pr)Cy, and LiNEt2, Lithium 2,2,6,6-Tetramethylpiperidide (LiTMP) was reported to be the best reagent for these processes.

Deprotonation of allyl chlorides with Cy2NLi gives a lithiated carbenoid intermediate which has been silylated to give an allyl halosilane, which can subsequently be used in reactions with carbonyl and acetal substrates (eq 9).4 Allylsilanes can be used in a number of synthetically useful transformations.17

More recently the carbenoid intermediate, prepared from allyl chloride and Cy2NLi, has been reacted with 9-methoxy-9BBN to give the homologous boron product (1) (eq 10). This can in turn undergo a number of transformations to give cyclooctane derivatives (eqs 11-13).5

In these transformations, Cy2NLi was the reagent of choice as other bases (LiNEt2, Lithium Pyrrolidide, LiN(t-Bu)SiMe3) gave reduced yields due to the problems of nucleophilic displacement of the methoxy group from the boron atom.

Deprotonation of Alkyl Boron Compounds.

Lithium dicyclohexylamide has been used in the formation of a-boron anion intermediates, the reactions of which have been extensively studied (eqs 14-17).8,12 In the coupling of the a-boron anion with metal compounds, a number of reagents and metals have been used, with HgCl2 giving the lowest yields.

In these studies, good yields were obtained with Cy2NLi, although Mesityllithium gave more consistent results. LiTMP has also been used in studies in this area.18

Miscellaneous.

Extensive studies of the reaction of lithium amides with carbon monoxide at atmospheric pressure have led to the formation of formamides (2), glyoxylamides (3), tetraalkylureas (4), tartronamides (5) and oxomalonamides (6) with good selectivity depending on the conditions of the reaction and workup (eq 18) (Table 1).10,14

One example of the use of Cy2NLi in studies with nonbenzenoid aromatic compounds has been reported. These results examined the deprotonation and carbonylation of a variety of azulenes (eqs 19 and 20). Good yields of the monocarboxy products were obtained, although the di- and triesters were also formed with azulene.9

One example of the use of Cy2NLi for dehydrochlorination has also been reported, giving the selective formation of trans-cyclodecene (eq 21) (cf. t-BuOK, eq 22).19


1. Hellou, J.; Kingston, J. F.; Fallis, A. G. S 1984, 1014.
2. Shimoji, K.; Taguchi, H.; Oshima, K.; Yamamoto, H.; Nozaki, H. JACS 1974, 96, 1620.
3. Olofson, R. A.; Dougherty, C. M. JACS 1973, 95, 582.
4. Hosomi, A.; Ando, M.; Sakurai, H. CL 1984, 1385.
5. Brown, H. C.; Jayaraman, S. JOC 1993, 58, 6791.
6. Taguchi, H.; Yamamoto, H.; Nozaki, H. JACS 1974, 96, 3010.
7. Clinet, J. C.; Linstrumelle, G. TL 1978, 1137.
8. (a) Pelter, A.; Singaram, B.; Warren, L.; Wilson, J. W. T 1993, 49, 2965. (b) Pelter, A.; Warren, L.; Wilson, J. W. T 1993, 49, 2988. (c) Pelter, A.; Warren, L.; Wilson, J. W. T 1993, 49, 3007.
9. McDonald, R. N.; Petty, H. E.; Wolfe, N.; Paukstelis, J. V. JOC 1974, 39, 1885.
10. Nudelman, N.; Lewkowicz, E. S.; Perez, D. G. S 1990, 917, and references cited therein.
11. Lochmann, L.; Trekoval, J. JOM 1979, 179, 123.
12. Wilson, J. W.; Pelter, A.; Garad, M. V.; Pardasani, R. T 1993, 49, 2979.
13. Aldrich Chemical Co.; Material Safety Data Sheet.
14. Furlong, J. J. P.; Lewkowicz, E. S.; Nudelman, N. S. JCS(P2) 1990, 1461.
15. For example, see: Leroux, Y.; Chantal, C. TL 1973, 2585.
16. Taguchi, H.; Yamamoto, H.; Nozaki, H. JACS 1974, 96, 6510.
17. For reviews on this area, see: (a) Yamamoto, Y.; Asao, N. CRV 1993, 93, 2207. (b) Fleming, I. T 1988, 44, no. 13. (c) Fleming, I. COS 1991, 2, 563.
18. Rathke, M. W.; Kow, R. JACS 1972, 94, 6854.
19. Traynham, J. G.; Stone, D. B.; Couvillan, J. L. JOC 1967, 32, 510.

Nat Monck

The Ohio State University, Columbus, OH, USA



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