[-] · 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
Daniel L. Comins & Sajan P. Joseph
North Carolina State University, Raleigh, NC, USA