[-]  · C5H13LiN2  · N-Lithio-N,N,N-trimethylethylenediamine  · (MW 108.14)

(reagent for the in situ formation of a-amino alkoxides, which are effective directing groups for ortho lithiation1)

Alternate Name: LTMDA.

Preparative Methods: prepared in situ by adding n-BuLi to N,N,N-trimethylethylenediamine in anhydrous solvents.

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

The title reagent (1) is an excellent reagent for in situ protection of aldehydes.1 Low temperature ortho lithiation/alkylation of aryl aldehydes can be achieved via an a-amino alkoxide intermediate generated by treating the aldehyde with LTMDA. The use of reagent (1) results in better yields of ortho-substituted products as compared to other reagents like Lithium N-Methylpiperazide and Lithium Morpholide.1 The ortho-lithiated intermediates can be trapped with various electrophiles (eq 1).2

The effectiveness of the ortho lithiations is attributed to an intramolecular TMEDA-like assisted metalation leading to a chelated intermediate such as (2) (eq 2).2 A similar methodology has been used for metalating benzylic carbons (eq 3).3

The versatility of reagent (1) has been demonstrated in the regioselective lithiation of various heterocycles.1 Thiophene-2-carbaldehyde and 2-furaldehydes undergo regioselective ortho substitution via ortho-lithiated LTMDA-derived a-amino alkoxides (eq 4).4

The scope of this reaction has been established by regioselectively metalating other regioisomers of the above mentioned aldehydes in excellent yields.4 Indole-2-carbaldehyde behaved in a similar manner.4 Interestingly, the N-methyl group of N-methylpyrrole-2-carbaldehyde underwent metalation with LTMDA/n-Butyllithium (eq 5).4

Under similar reaction conditions, N-methylindole-2-carbaldehyde is known to give products resulting from ring-lithiated and N-methyl-lithiated intermediates.5 This selectivity problem was solved by using 3-chloro-N-methylindole-2-carbaldehyde, which gave exclusive N-methyl lithiation.5 Regioselective lithiation of a-amino alkoxides prepared from methoxypyridinecarbaldehydes can be achieved in good yield (Scheme 1).6 Regioselective substitution of a 1-(Boc)-3-formyl-1,4-dihydropyridine has been carried out using (1) and Mesityllithium as the base.7

LTMDA has been successfully utilized in the synthesis of schumanniophytine, isoschumanniophytine,8a and maxonine.8b A directed lithiation using an LTMDA-derived a-amino alkoxide was a key step in a short, asymmetric synthesis of (S)-camptothecin.9 For another reagent similar to LTMDA, see Lithium N-Methylpiperazide.1

1. Comins, D. L. SL 1992, 615.
2. (a) Comins, D. L.; Brown, J. D. JOC 1984, 49, 1078. (b) Peet, N. P.; McCarthy, J. R.; Sunder, S.; McCowan, J. SC 1986, 16, 1551. (c) Comins, D. L.; Brown, J. D. JOC 1989, 54, 3730.
3. Comins, D. L.; Brown, J. D. JOC 1986, 51, 3566.
4. Comins, D. L.; Killpack, M. O. JOC 1987, 52, 104.
5. Comins, D. L.; Killpack, M. O. TL 1989, 30, 4337.
6. Comins, D. L.; Killpack, M. O. JOC 1990, 55, 69.
7. Comins, D. L.; Weglarz, M. A. JOC 1988, 53, 4437.
8. (a) Kelly, T. R.; Kim, M. H. JOC 1992, 57, 1593. (b) Kelly, T. R.; Xu, W.; Sundaresan, J. TL 1993, 34, 6173.
9. Comins, D. L.; Baevsky, M. F.; Hong, H. JACS 1992, 114, 10971.

Daniel L. Comins & Sajan P. Joseph

North Carolina State University, Raleigh, NC, USA

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