Lithium 2,2,6,6-Tetramethylpiperidide

[38227-87-1]  · C9H18LiN  · Lithium 2,2,6,6-Tetramethylpiperidide  · (MW 147.22)

(strong, highly hindered, nonnucleophilic base (pKa = 37.3)1 capable of selective deprotonation of aromatics, heteroaromatics, and aliphatic C-H acidic sites in the presence of a variety of functional groups; also compatible with several electrophiles for in situ quenching of kinetically derived lithiated species2-5)

Alternate Names: LiTMP; LTMP.

Physical Data: exists in THF solution as a dimer-monomer equilibrium mixture; additives such as HMPA increase monomer concentration.6,7 X-ray structure determination shows that LiTMP crystallizes as a tetramer from hexane/pentane mixtures.8

Solubility: sol most organic solvents including THF, Et2O, hexane.

Preparative Method: prepared in Et2O or THF solutions immediately before use by treatment of commercially available dry 2,2,6,6-Tetramethylpiperidine with n-Butyllithium (1:1). Tetramethylpiperidine is dried by heating a mixture of the base with CaH2 at reflux for 4 h in a preflamed flask, followed by distillation at atmospheric pressure (bp 152 °C). It should be stored in a septum sealed bottle.

Handling, Storage, and Precautions: LiTMP solutions are pyrophoric, can cause severe burns, and should always be handled and transferred under an inert atmosphere. Solutions of LiTMP show a loss of activity (50% in THF; 60% in Et2O) after 12 h at 24 °C.9 Use in a fume hood.

Benzyne Formation.

The earliest uses of LiTMP as a base involved the deprotonation of benzyl chloride to give phenylcarbene and of 2-chloroanisole to give 3-methoxybenzyne.10 LiTMP may also be used for heteroaryne generation; for example, treatment of 1,3-bis(TMS)isobenzofuran with 3-bromopyridine in the presence of LiTMP gives the corresponding cycloaddition product (eq 1).11

In situ Compatibility with Electrophiles.

Martin first demonstrated that the low nucleophilicity of LiTMP makes it compatible, at low temperatures, with certain electrophiles, e.g. Chlorotrimethylsilane, Trimethyl Borate.2a This allows the preparation of 2- and 2,6-silylated benzoates and benzonitriles by equilibrium controlled ortho-lithiation processes (eq 2). The distribution of mono- and disilylated products may be controlled by the number of equivalents of LiTMP; these products may be converted into corresponding bromo and iodo derivatives by ipso-halodesilylation.2a,12 Similar Lithium Diisopropylamide-TMSCl compatibility has been demonstrated.5,13

Analogous use of the LiTMP-Mercury(II) Chloride combination allows selective functionalization of cubanecarboxamides (eq 3) and cyclopropanecarboxamides (eq 4),14,15 presumably as a consequence of the high s character of the C-H bonds in these systems.

Application of Martin's conditions to N,N-dimethylbenzamide leads, surprisingly, to a,a-disilylation in good yield (eq 5).16 Further treatment with LiTMP/TMSCl gives the ortho-silylated product. The bis-TMS derivative serves as a useful directed metalation group and may be readily converted to benzoic acid, benzaldehyde, and benzyl alcohol derivatives.

Remote Metalation.

LiTMP may be used interchangeably with LDA to effect conversion of diaryl amides into fluorenones by virtue of a complex induced proximity effect (eq 6).17 This general route complements Friedel-Crafts chemistry for the preparation of fluorenones.

Directed ortho Metalation.

N-t-Boc-pyrrole undergoes clean deprotonation with LiTMP.18 Low-temperature LiTMP lithiation of pyrazinecarboxamide followed by deuteration leads to isomeric products reflecting the temperature at which the reaction is quenched (eq 7).3 This is rationalized by the thermodynamic stability of the ortho-amido lithiated species at the higher temperature.

The use of LiTMP in heterocyclic directed ortho-metalation chemistry is advantageous. For example, pyridine amide and oxazoline derivatives are smoothly deprotonated and lead, after electrophile quench, to 4-substituted products (e.g. eq 8),19 which may be used for the synthesis of natural products (e.g. eq 9) and pharmaceuticals.20-22 In contrast to LDA and, of course, alkyllithiums, no nucleophilic attack of the pyridine ring is observed.19 The considerable C-H acidity of methylpyridines allows deprotonation-condensation reactions which are of general synthetic value (eq 9).20

In some cases, LiTMP complements the metalation regioselectivity of LDA. For example, LDA metalation of 2,4-dichloropyrimidine gives the 5-substituted product whereas LiTMP affords mainly the product of 6-substitution (eq 10).23

Enolate Formation.

LiTMP is widely used to generate a-stabilized carbanions. For example, in the synthesis of paniculide A, the use of LiTMP is critical; LDA fails to give the required product (eq 11).24

LiTMP is especially useful in cases where the reactants are sensitive to nucleophilic attack (e.g. eq 12) (cf. 66% yield with LDA).10

LiTMP is also used to deprotonate nonenolizable sites. For example, bridgehead deprotonation of (-)-camphenilone is followed by self-condensation to give a high yield of dimeric product (eq 13).25

Under similar conditions, LiTMP generates the acyllithium of a nonenolizable aldehyde which undergoes self-condensation to give an acyloin (eq 14).25

The primary reservation concerning the use of LiTMP in synthesis, particularly on a large scale, is the cost of tetramethylpiperidine relative to other amine bases. However, an aqueous acid extraction of the reaction mixture allows the recovery of tetramethylpiperidinium salt from which the free base can be obtained by neutralization and distillation. This recovery method is dependent on the acid stability of the reaction products.

Related Reagents.

Lithium Diethylamide; Lithium Diisopropylamide; Lithium Hexamethyldisilazide; Lithium Piperidide; Lithium Pyrrolidide.

1. Fraser, R. R.; Mansour, T. S. JOC 1984, 49, 3443.
2. (a) Krizan, T.; Martin, J. C. JACS 1983, 105, 6155. (b) Krizan, T. D.; Martin, J. C. JOC 1982, 47, 2681. (c) Fraser, R. R.; Savard, S. CJC 1986, 64, 621.
3. Turck, A.; Plé, N.; Trohay, D.; Ndzi, B.; Quéguiner, G. JHC 1992, 29, 699.
4. Beak, P.; Lee, B. JOC 1989, 54, 458.
5. Eaton, P. E.; Martin, R. M. JOC 1988, 53, 2728.
6. Renaud, P.; Fox, M. A. JACS 1988, 110, 5705.
7. Romesberg, F. E.; Gilchrist, J. H.; Harrison, A. T.; Fuller, D. J.; Collum, D. B. JACS 1991, 113, 5751.
8. Lappert, M. F.; Slade, M. J.; Singh, A. JACS 1983, 105, 302.
9. Kopka, I. E.; Fataftah, A.; Rathke, M. W. JOC 1987, 52, 448.
10. Olofson, R. A.; Dougherty, C. M. JACS 1973, 95, 582.
11. Crump, S. L.; Netka, J.; Rickborn, B. JOC 1985, 50, 2746.
12. Unrau, C. M.; Campbell, M. G.; Snieckus, V. TL 1992, 23, 2773.
13. Corey, E. J.; Gross, A. W. TL 1984, 25, 495.
14. Eaton, P. E.; Castaldi, G. JACS 1985, 107, 724.
15. Eaton, P. E.; Daniels, R. G.; Casucci, D.; Cunkle, G. T.; Engel, P. JOC 1987, 52, 2100.
16. Cuevas, J.-C.; Patil, P.; Snieckus, V. TL 1989, 30, 5841.
17. Zhao, B.; Snieckus, V., unpublished results.
18. Hasan, I.; Marinelli, E. R.; Lin, L.-C. C.; Fowler, F. W.; Levy, A. B. JOC 1981, 46, 157.
19. Meyers, A. I.; Gabel, R. A. JOC 1982, 47, 2633.
20. Iwao, M.; Kuraishi, T. TL 1983, 24, 2649.
21. Watanabe, M.; Shinoda, E.; Shimizu, Y.; Furukawa, S.; Iwao, M.; Kuraishi, T. T 1987, 43, 5281.
22. Dunbar, P. G.; Martin, A. R. H 1987, 26, 3165.
23. Plé, N.; Turck, A.; Martin, P.; Barbey, S.; Quéguiner, G. TL 1993, 34, 1605.
24. Smith, A. B., III; Richard, R. E. JOC 1981, 46, 4814.
25. Shiner, C. S.; Berks, A. H.; Fisher, A. M. JACS 1988, 110, 957.

Mike Campbell & Victor Snieckus

University of Waterloo, Ontario, Canada

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