Lithium N-Methylpiperazide

[105563-31-3]  · C5H11LiN2  · Lithium N-Methylpiperazide  · (MW 106.12)

(in situ protection of aryl aldehydes via a-amino alkoxide formation; a-amino alkoxides can direct or block ortho-lithiation1)

Alternate Name: LNMP.

Preparative Method: prepared in situ by adding n-Butyllithium to N-methylpiperazine in anhydrous solvents.

Handling, Storage, and Precautions: highly flammable; should be kept under a nitrogen or argon atmosphere.

Lithium N-methylpiperazide is conveniently used as a reagent for in situ protection of aryl aldehydes through a-amino alkoxide formation.1 Stability of LNMP-derived a-amino alkoxides to alkyllithium reagents and their solubility in organic solvents are reasons why LNMP is preferred over similar reagents.1 The a-amino alkoxides obtained in situ from substituted benzaldehydes are not easily ortho-lithiated; however, refluxing a benzene solution of the a-amino alkoxide and excess n-Butyllithium for 3-12 h effects ortho-metalation. Addition of excess electrophile followed by aqueous workup gives moderate to good yields of the desired ortho-substituted aryl aldehydes (eq 1).2

Regioselective substitution of bis-activated benzaldehydes can be achieved by lithiation/alkylation of an a-amino alkoxide obtained from LNMP. p-Anisaldehyde, on treatment with LNMP and s-Butyllithium in the presence of N,N,N,N-Tetramethylethylenediamine and subsequent quenching with Iodomethane, gives 4-methoxy-3-methylbenzaldehyde (eq 2).3 This is in sharp contrast to the analogous reaction using N-Lithio-N,N,N-trimethylethylenediamine (LTMDA) in place of LNMP, where 4-methoxy-2-methylbenzaldehyde is produced in good yield.1 Under the same reaction conditions, o- and m-anisaldehydes give C-3 and C-4 lithiated products, respectively. Both 3,5- and 2,4-dimethoxybenzaldehydes can be metalated between the methoxy substituents in excellent yield using LNMP, s-BuLi, and TMEDA.

Heterocyclic aldehydes can be metalated regioselectively using similar methodology to that described above.4 For example, 2-thiophenecarbaldehyde on reaction with LNMP, n-BuLi, and TMEDA and subsequent quenching with iodomethane, gives 5-methyl-2-thiophenecarbaldehyde in 77% yield (eq 3).

When LTMDA is used instead of LNMP, a mixture of 3- and 5-methyl-2-thiophenecarbaldehydes is obtained. However, 3-thiophenecarbaldehyde and LNMP under similar reaction conditions give a mixture of C-5 and C-2 substituted products in a ratio of 83:17. Alkylation of 2-furaldehyde occurs exclusively at the 5-position when treated with LNMP, n-butyllithium, and iodomethane.4 In a similar manner, 3-furaldehyde gives mainly C-2 alkylation, but 2-methyl-3-furaldehyde, on treatment with LNMP, n-BuLi, and iodomethane, gives 2,5-dimethyl-3-furaldehyde in 50% yield. Using similar reaction conditions, N-methylpyrrole-2-carbaldehyde and N-methylindole-2-carbaldehyde give the corresponding C-5 and C-3 substituted products on reaction with LNMP, n-BuLi, TMEDA, and iodomethane.4 Interestingly, methoxypyridinecarbaldehydes, on treatment with LNMP, alkyllithium, and TMEDA, give metalation ortho to the methoxy group (Scheme 1).5 This is in sharp contrast to LTMDA-assisted metalations, where substitution occurs ortho to the aldehyde group.

A regioselective lithiation/alkylation of a 1-Boc-3-formyl-1,4-dihydropyridine has been effected using LNMP and Mesityllithium as the base.6 Dealkylation of several o-alkoxyaryl aldehydes can be achieved via the corresponding a-amino alkoxides prepared with LNMP.7

Related Reagents.

N-Lithio-N,N,N-trimethylethylenediamine; Lithium Morpholide.


1. Comins, D. L. SL 1992, 615.
2. Comins, D. L.; Brown, J. D. TL 1981, 22, 4213.
3. Comins, D. L.; Brown, J. D. JOC 1984, 49, 1078.
4. Comins, D. L.; Killpack, M. O. JOC 1987, 52, 104.
5. Comins, D. L.; Killpack, M. O. JOC 1990, 55, 69.
6. Comins, D. L.; Weglarz, M. A. JOC 1988, 53, 4437.
7. Gillies, B.; Loft, M. S. SC 1988, 18, 191.

Daniel L. Comins & Sajan P. Joseph

North Carolina State University, Raleigh, NC, USA



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