N-t-Butoxycarbonyl-N-methylaminomethyllithium1

[-]  · C7H14LiNO2  · N-t-Butoxycarbonyl-N-methylaminomethyllithium  · (MW 151.13)

(a-amino carbanion nucleophile for displacement and addition reactions1)

Alternate Name: N-Boc-a-lithiodimethylamine.

Preparative Methods: can be prepared by stirring N-Boc-dimethylamine with s-Butyllithium at -50 °C in THF for 2 h. The organolithium reagent reacts with electrophiles to provide substitution products in good yields. N-Boc-dimethylamine can be prepared from the reaction of Potassium t-Butoxide and Dimethylcarbamoyl Chloride in THF.

a-Amino Organolithium Reagents.

a-Amino organolithium reagents useful for the elaboration of amines via a-amino carbanion synthetic equivalents can be prepared from N-Boc secondary amines which bear a methyl or methylene group. The general application of this methodology for amine elaboration is shown in eq (1). Lithio derivatives of N-benzyloxycarbonyl (Cbz) and N-methoxycarbonyl amines can also be generated by tin-lithium exchange reactions.2 The generation and use of other N-substituted organometallic reagents has been reviewed.3

Conversion to the a-lithioamine synthetic equivalents is achieved by reaction with s-Butyllithium or s-BuLi/N,N,N,N-Tetramethylethylenediamine in diethyl ether or THF at low temperatures.1 Addition of electrophiles provides the a-substituted N-Boc amines in good yields. The N-Boc groups can be cleaved under acidic or basic conditions to provide the elaborated secondary amines. It is important that the solvent and reagents be anhydrous and the s-BuLi be of good quality. A specific case for the key steps of lithiation and substitution for t-butoxycarbonyl-N-methylaminomethyllithium is shown in eq (2). Selectivity for the less substituted position is usually observed as shown in eq (3).

Extensions of this methodology to heterocyclic amines have been achieved with control of stereochemistry. Lithiation of N-Boc-piperidine followed by electrophilic substitutions provide 2-substituted N-Boc-piperidines. When the electrophile is an aldehyde, the syn and anti isomers are obtained in ca. 1:1 ratio. Lithiation and substitution of 4-substituted N-Boc-piperidines gives diequatorial cis-2,4-disubstituted N-Boc-piperidines.4 Lithiation and substitution of 2-substituted N-Boc-piperidines provides trans-2,6-disubstituted piperidines. The stereochemical outcome is consistent with equatorial lithiation and substitution with retention of configuration of the carbon-lithium bond (eq 4). The 2-substituted N-Boc-piperidine undergoes lithiation to generate a 2-axial substituent because of allylic (A1,3) strain. This methodology has been used to prepare a 2,6-trans-disubstituted piperidine alkaloid, solenopsin A, from N-Boc-piperidine.4 By taking advantage of the equilibration of a trans-2,6-disubstituted piperidine to the more stable cis isomer, a derivative of a cis-2,6-disubstituted piperidine alkaloid, the author also prepared cis-dihydropinidine.5 Similar lithiation-substitution sequences have been reported with N-Boc-pyrrolidine and N-Boc-perhydroazepine.5

With a leaving group adjacent to the site of lithiation, elimination can occur followed by a second lithiation; for 3-methoxy-N-Boc-piperidine with 2 equiv of s-BuLi, N-Boc-2-substituted D2-piperidines are obtained (eq 5).5

High enantioselectivities are observed in the lithiation-substitution sequence when s-BuLi/(-)-Sparteine is used as the lithiating base for N-Boc-pyrrolidine (eq 6).6 The sequence proceeds by an asymmetric deprotonation to provide an enantioenriched organolithium intermediate which maintains configuration and reacts with electrophiles stereoselectively to give highly enantioenriched products.6 Repetition of this sequence for a second substitution with enantioenriched reactant gives a substantial amplification of enantioenrichment of (S,S)-2,5-dimethyl-N-Boc-pyrrolidine (eq 7).7

Related Reagents.

Diphenyl(methoxymethyl)phosphine; s-Butyllithium; Dimethylaminomethyllithium; N-Nitrosodimethylamine; N,N,N,N-Tetramethylethylenediamine.


1. Beak, P.; Lee, W. K. TL 1989, 30, 1197.
2. (a) Pearson, W. H.; Lindbeck, A. C. JOC 1989, 54, 5651. (b) Pearson, W. H.; Lindbeck, A. C.; Kampf, J. W. JACS 1993, 115, 2622.
3. For summaries of related methodology, see (a) Beak, P.; Zajdel, W. J.; Reitz, D. B. CRV 1984, 84, 471. (b) Gawley, R. E.; Rein, K. COS, 1991, 1, 65, 459. (c) Hart, D. J. In Alkaloids; Chemical and Biological Perspectives, Pelletier, S. W., Ed.; Wiley: New York, 1988; Vol. 6, p 227. (d) Hishsmith, T. K.; Meyers, A. I. In Advances in Heterocyclic Natural Products Synthesis; Pearson, W. H., Ed.; JAI: Greenwich, CT, 1990; Vol. 1, p 94.
4. Beak, P.; Lee, W. K. JOC 1990, 55, 2578.
5. Beak, P.; Lee, W. K. JOC 1993, 58, 1109.
6. Kerrick, S. T.; Beak, P. JACS 1991, 113, 9708.
7. Beak, P.; Kerrick, S. T.; Wu, S.; Chu, J. JACS 1994, 116, 3231.

Peter Beak

University of Illinois at Urbana-Champaign, IL, USA

Won Koo Lee

Sogang University, Seoul, Korea



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