2,2,6,6-Tetramethylpiperidine

[768-66-1]  · C9H19N  · 2,2,6,6-Tetramethylpiperidine  · (MW 141.29)

(hindered secondary amine used in preparing metallo-amide bases; selective generation of silylketene acetals)

Alternate Name: TMP.

Physical Data: bp 155.5-156.5 °C; fp 24 °C; d 0.837 g cm-3.

Solubility: sol most organic solvents.

Purification: by distillation.

Handling, Storage, and Precautions: liquid is corrosive and flammable. Bottles of 2,2,6,6-tetramethylpiperidine should be flushed with nitrogen or argon to prevent exposure to carbon dioxide. The vapors are harmful and care should be taken to avoid absorption through the skin. Use in a fume hood.

Silylketene Acetal Preparations.

This reagent finds utility in the selective preparation of (Z)-silylketene acetals from simple alkyl esters and Triethylsilyl Perchlorate under kinetic conditions.1 In a comparison with Triethylamine and Diisopropylethylamine (DIPEA), 2,2,6,6-tetramethylpiperidine was found to be the superior base for generating the (Z)-silylketene acetal of isopropyl propanoate using triethylsilyl perchlorate in CHCl3 at -70 °C (eq 1). Isomerization (equilibration) is not observed under these reaction conditions (see Diisopropylethylamine for discussion on similar base-controlled generation of boron enolates).

Amide Base Preparation.

The hindered base can easily be converted to stronger metallo-amide bases while retaining nonnucleophilic character. Treatment of TMP with organolithium reagents generates Lithium 2,2,6,6-Tetramethylpiperidide (LTMP),2 which finds application in synthesis when a strong base (LTMP, pKa &AApprox; 37.3)3 is required.4 However, LTMP has been shown to be somewhat nucleophilic. Treatment of the trifluoromethylamidine (1) with a five-fold excess of LTMP in benzene at 50 °C5 affords the 4-substituted quinazoline (2) in 36% yield. The mechanism involves sequential addition of multiple equivalents of LTMP (eq 2).6

TMP generates, when treated with 1 equiv of Ethylmagnesium Bromide or 0.5 equiv of Dibutylmagnesium in refluxing THF, the amido-Grignard reagent N-(bromomagnesio)-2,2,6,6-tetramethylpiperidide (TMPMgBr) and the magnesium amide base bis(2,2,6,6-tetramethylpiperidino)magnesium ((TMP)2Mg), respectively. The TMPMgBr base finds use in selective enolate formation,7 while the bis magnesium base, (TMP)2Mg, succeeds at ortho metalation by magnesium of benzamides (eq 3) and aromatic esters (eq 4).8

LTMP can be converted to dialkylaluminum amides (e.g. Diethylaluminum 2,2,6,6-Tetramethylpiperidide) by treatment with dialkylaluminum chloride in toluene. Reaction of LTMP with diisobutylaluminum chloride yields diisobutylaluminum 2,2,6,6-tetramethylpiperidide (i-Bu2AlTMP), which has utility in the diastereoselective cleavage of acetals to chiral nonracemic enol ethers (eq 5).9

Proton Abstraction.

The nonnucleophilic character of the base TMP makes it an ideal choice in alkylations involving reactive electrophiles. This is evident in the cycloaddition reaction between the trithiadiazepine (3) and the highly reactive 1,3-diphenylisobenzofuran involving the intermediacy of the base-induced hetaryne (4) (eq 6).10 Use of TMP in the reaction gives the cycloaddition product (6), whereas use of a more nucleophilic base, Morpholine, results in the morpholino derivative (5) as the major product. However, when the hetaryne (4) reacts with a less reactive diene, such as tetraphenylcyclopentadienone, the major isolated product is the tetramethylpiperdino derivative (5) (NR2 = TMP).11

Though TMP is considered nonnucleophilic, it can be alkylated (eq 7)12 and sulfenylated.13 Chlorination, using sodium dichloroisocyanurate, leads to N-chloro-2,2,6,6-tetramethylpiperidine,14 which has found limited use in regiospecific chlorinations.15 Also, treatment of TMP with trifluoroamine oxide produces the N-fluoro and N-nitroso derivatives,16 while treatment with N,O-Bis(trimethylsilyl)acetamide and Methyl Chloroformate affords the methyl carbamate derivative in 65% yield.17 The reaction of TMP with diethyl phosphonomethyltriflate in ether at 0 °C for just 30 min leads to the N-(diethyl phosphonomethyl)-TMP derivative in excellent yield (eq 7).18

Oxidation.

N-Hydroxy-2,2,6,6-tetramethylpiperidine is oxidatively converted to the stable nitroxyl radical 2,2,6,6-Tetramethylpiperidin-1-oxyl,19 which is useful as a spin label or trap, and a catalyst for selective oxidation of alcohols.20


1. Wilcox, C. S.; Babston, R. E. TL 1984, 25, 699.
2. (a) Olofson, R. A.; Dougherty, C. M. JACS 1973, 95, 581. (b) Olofson, R. A.; Dougherty, C. M. JACS 1973, 95, 582. (c) Kopka, I. E.; Fataftah, Z. A.; Rathke, M. W. JOC 1987, 52, 448. (d) Einhorn, J.; Luche, J. L. JOC 1987, 52, 4124. (e) Podraza, K. F.; Bassfield, R. L. JOC 1988, 53, 2643. (f) Einhorn, C.; Einhorn, J.; Luche, J.-L. S 1989, 787. (g) De Nicola, A.; Einhorn, J.; Luche, J.-L. JCR(S) 1991, 278.
3. (a) Fraser, R. R.; Mansour, T. S. JOC 1984, 49, 3443. (b) Fraser, R. R.; Mansour, T. S.; Savard, S. JOC 1985, 50, 3232. See also (c) Grimm, D. T.; Bartmess, J. E. JACS 1992, 114, 1227.
4. For just a sampling of the uses of LTMP, see: (a) Rathke, M. W.; Kow, R. JACS 1972, 94, 6854. (b) Harmon, A. D.; Hutchinson, C. R. JOC 1975, 40, 3474. (c) Newcomb, M.; Reeder, R. A. JOC 1980, 45, 1489. (d) Tuschka, T.; Naito, K.; Rickborn, B. JOC 1983, 48, 70. (e) Eaton, P. E.; Castaldi, G. JACS 1985, 107, 724. (f) Ward, J. S.; Merritt, L. JHC 1991, 28, 765. (g) Bartoli, G.; Bosco, M.; Cimarelli, C.; Dalpozzo, R.; Palmieri, G. SL 1991, 229.
5. LTMP decomposes above 0 °C in THF. See Eaton, P. E.; Higuchi, H.; Millikan, R. TL 1987, 28, 1055.
6. Patterson, S. E.; Janda, L.; Strekowski, L. JHC 1992, 29, 703.
7. Van Draanen, N. A.; Arseniyadis, S.; Crimmins, M. T.; Heathcock, C. H. JOC 1991, 56, 2499.
8. Eaton, P. E.; Lee, C.-H.; Xiong, Y. JACS 1989, 111, 8016.
9. (a) Maruoka, K.; Yamamoto, H. AG(E) 1985, 24, 668. (b) Naruse, Y.; Yamamoto, H. T 1988, 44, 6021.
10. Plater, J. M.; Rees, C. W. JCS(P1) 1991, 301.
11. Plater, J. M.; Rees, C. W. JCS(P1) 1991, 317.
12. Phillion, D. P.; Andrew, S. S. TL 1986, 27, 1477.
13. (a) Ikehira, H.; Tanimoto, S. S 1983, 716. (b) Branchaud, B. P. JOC 1983, 48, 3538.
14. Zakrewski, J. SC 1988, 18, 2135 and references cited therein.
15. (a) Deno, N. C.; Gladfelter, E. J.; Pohl, D. G. JOC 1979, 44, 3728. (b) Deno, N. C.; Pohl, D. G.; Spinelli, H. J. Bioorg. Chem. 1974, 3, 66.
16. Gupta, O. D.; Kirchmeier, R. L.; Shreeve, J. M. JACS 1990, 112, 2383.
17. Raucher, S.; Jones, D. S. SC 1985, 15, 1025.
18. Phillion, D. P.; Andrew, S. S. TL 1986, 27, 1477.
19. For reviews, see: (a) Rozantsev, E. G.; Sholle, V. D. S 1971, 190. (b) Keana, J. F. W. CRV 1978, 78, 37.
20. (a) Anelli, P. L.; Montanari, F.; Quici, S. OS 1990, 69, 212; OSC 1993, 8, 367. (b) Siedlecka, R.; Skarzewski, J.; Mlochowski, J. TL 1990, 31, 2177. (c) Anelli, P. L.; Banfi, S.; Montanari, F.; Quici, S. JOC 1989, 54, 2970, and references cited therein.

Kirk L. Sorgi

The R. W. Johnson Pharmaceutical Research Institute, Spring House, PA, USA



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