Dimethylaminomethyllithium

Me2NCH2Li

[26285-58-5]  · C3H8LiN  · Dimethylaminomethyllithium  · (MW 65.06)

(agent for nucleophilic dialkylaminomethylation; regioselective preparation of 2-dialkylamino alcohols)

Physical Data: the X-ray structure of the ether-complexed dimer of N,N-dimethylaminobenzyllithium1a and its structure in solution (1H, 13C NMR)1b have been reported. The pKa of its potassium salt has been determined to be 41.1.1c

Solubility: sol THF and ether.

Form Supplied in: prepared in situ by the methods described below and used directly.

Handling, Storage, and Precautions: must be prepared and handled under inert gas (Ar) to exclude oxygen and moisture.

General Discussion.

The direct preparation of N,N-dialkylaminomethyllithium (2) by deprotonation of tertiary aliphatic methylamines (1) with alkyllithium bases is normally not possible. Thus dimethyldodecylamine is deprotonated by t-Butyllithium only to the extent of 7%.2a The slow deprotonation rate of (1) and the thermal instability of (2) prevent further enrichment in (2). To solve this problem, acceleration of metalation by activation of the base or the amine has been used.

With the stronger basic system s-Butyllithium/Potassium t-Butoxide the direct preparation of the potassium salts (4) from (1) is possible when excess amine is used as solvent (e.g. Triethylamine, N-methylpiperidine, N-methylpyrrolidine) (eq 1).2b The potassium salts can be alkylated but are strongly basic. Enolizable carbonyl compounds are only deprotonated. When the potassium salts are treated with Lithium Bromide in ether, the more nucleophilic lithium salts (2) are formed and hydroxyalkylation to give 2-amino alcohols (3) is possible even with acidic carbonyl compounds such as cyclohexenone.

The easiest way to activate the amines consists of complexation with Boron Trifluoride prior to metalation to give, after deprotonation with s-butyllithium, a sort of dipole-stabilized3 anion (6), as demonstrated for N-methylpyrrolidine and N-methylpiperidine.4 After quenching with benzaldehyde, benzophenone, or cyclohexanone the corresponding 2-amino alcohols (3) have been obtained in good yields (eq 2). Alkylation with Iodomethane (51%), oxidation with Iodine to give the 1,2-diamine (65%), and acylation with benzonitrile (50%) or Methyl Acrylate (69%) are also reported.

To avoid the difficulties of direct deprotonation, the very fast method of tin-lithium exchange can be used. From a-stannylated amines (7) the a-lithioamines (2) are available immediately with n-Butyllithium in hexane (e.g. trimethylamine, N-methylpiperidine, N,N-dimethylaniline, N-methyldiphenylamine) and can be trapped with benzaldehyde to give the amino alcohols (8) in high yields (eq 3).5 The only exception observed has been with N-lithiomethylmorpholine, which decomposed rapidly.

The method has been extended to other N-methylamines, of which N-benzyldimethylamine is the most interesting, since after electrophilic reaction the benzyl group can be removed reductively to give formally the product of a-lithiodimethylamine. After reaction at -65 °C with Chlorotrimethylsilane, the silylated amine is obtained in 87% yield. However, after warming to rt for 1 h, only the product of a Wittig rearrangement is found.6 For comparison of the three methods see Table 1.

Some further synthetic applications are given in eqs 4 and 5.7,8

The a-stannylated amines (7) are best prepared by addition of Tri-n-butylstannyllithium to S,N-acetals (50-75%)5,6 or tributylstannylmagnesium chloride to O,N-acetals (65-89%)7 or immonium salts (75-89%).8

Another way to accelerate metalation is through intramolecular complexation:9 N,N,N,N-Tetramethylethylenediamine (TMEDA)10 or N,N,N,N,N-Pentamethyldiethylenetriamine (PMDTA)11 can be deprotonated at the methyl group with alkyllithiums in alkanes to give the corresponding aminoalkyllithiums; the latter can be trapped with Chlorotrimethylstannane or benzaldehyde. Lithiated PMDTA has been characterized by NMR methods and shown to be monomeric in solution.12

All reactions described so far are restricted to the generation of dialkylaminomethyllithiums and failed to generate homologous dialkylaminoalkyllithiums. This limitation can be overcome by acceleration of the tin-lithium exchange reaction by built-in complexing ligands, as for the generation of lithiated and configurationally stable aziridine reagents.13 The method has been exploited for the preparation of enantiomerically enriched aminoalkyllithium compounds to study their configurational stability (eq 6).14

More generally, secondary and even tertiary dialkylaminoalkyllithium reagents can be generated by reductive metalation of S,N-acetals with Lithium 4,4-Di-t-butylbiphenylide (LiDBB) (eq 7).15

Related Reagents.

N-t-Butoxycarbonyl-N-methylaminomethyllithium; N-t-Butyl-N-methyl-N-trimethylsilylmethylformamidine; N-Nitrosodimethylamine.


1. (a) Boche, G.; Marsch, M.; Harbach, J.; Harms, K.; Ledig, B.; Schubert, F.; Lohrenz, J. W. C.; Ahlbrecht, H. CB 1993, 126, 1887. (b) Ahlbrecht, H.; Harbach, J.; Hauck, T.; Kalinowski, H.-O. CB 1992, 125, 1753. (c) Ahlbrecht, H.; Schneider, G. unpublished results 1986.
2. (a) Peterson, D. J.; Hays, H. R. JOC 1965, 30, 1939. (b) Ahlbrecht, H.; Dollinger, H. TL 1984, 25, 1353.
3. The concept of dipole stabilization has been widely used for deprotonation of secondary amines: Beak, P.; Zajdel, W. J.; Reitz, D. B. CRV 1984, 84, 471.
4. Kessar, S. V.; Singh, P.; Vohra, R.; Kaur, N. P.; Singh, K. N. CC 1991, 568.
5. Peterson, D. J. JACS 1971, 93, 4027.
6. Peterson, D. J.; Ward, J. F. JOM 1974, 66, 209.
7. Quintard, J.-P.; Elissondo B.; Jousseaume, B. S 1984, 495.
8. Elissondo B.; Verlhac J.-B.; Quintard, J.-P.; Pereyre M. JOM 1988, 339, 267.
9. The CIPE effect: Beak, P.; Meyers, A. I. ACR 1986, 19, 356.
10. Köhler, F. H.; Hertkorn, N.; Blümel, J. CB 1987, 120, 2081.
11. Schakel, M.; Aarnts, M. P.; Klumpp, G. W. RTC 1990, 109, 305.
12. Klumpp, G. W.; Luitjes, H.; Schakel, M.; de Kanter, F. J. J.; Schmitz, R. F.; van Eikema Hommes, N. J. R. AG 1992, 104, 624.
13. Vedejs, E.; Moss, W. O. JACS 1993, 115, 1607.
14. Burchat A. F.; Chong J. M.; Park S. B. TL 1993, 34, 51.
15. Tsunoda, T.; Fujiwara, K.; Yamamoto Y.; Ito S. TL 1991, 32, 1975.

Hubertus Ahlbrecht

Justus Liebig University, Giessen, Germany



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