Structurally engineered deprotonation/alumination of THF and THTP with retention of their cycloanionic structures

Crosbie, Elaine and Garcia-Alvarez, Pablo and Kennedy, Alan R. and Klett, Jan and Mulvey, Robert E. and Robertson, Stuart D. (2010) Structurally engineered deprotonation/alumination of THF and THTP with retention of their cycloanionic structures. Angewandte Chemie International Edition, 49 (49). pp. 9388-9391. ISSN 1433-7851 (

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Metalation has served well for over 80 years as a vehicle for transforming inert C[BOND]H bonds in organic compounds to reactive C[BOND]metal bonds.1 Progress in metalation was accelerated greatly by the development of DoM (directed ortho-metalation),2 pioneered by Snieckus, Beak, and others, a special type of lithiation (aromatic C[BOND]H to Cδ−[BOND]Liδ+) reliant on the high polarity of carbon–lithium bonds in organolithium reagents. Many other metals could not engage in metalation due to the lower polarity/lower reactivity of their corresponding carbon–metal bonds. However, this obstacle has now been cleared by the recognition that when part of a mixed-metal system or other multicomponent mixture, these metals (for example, magnesium, zinc, aluminum or manganese) can exhibit greatly enhanced metalating properties often superior in terms of functional-group compatibility or reaction conditions to that of lithium. Interest in these new “low polarity” metalating agents is widespread with coverage in fundamental chemistry journals,3 process chemistry journals,4 interdisciplinary science journals,5 and in news items in scientific media.6 Knochel’s turbo-Grignard reagents (e.g., (iPr)MgCl⋅LiCl) 7 are examples that have been commercialized. A spectacular demonstration of the special reactivity of bimetallic bases came with the α-zincation of tetrahydrofuran (THF) by the sodium dialkyl(amido)zincate [(TMEDA)Na(μ-TMP)(μ-CH2SiMe3)Zn(CH2SiMe3)] (TMEDA=N,N,N′,N′-tetramethylethylenediamine; TMP=2,2,6,6-tetramethylpiperidine) to produce [(TMEDA)Na(μ-TMP)(μ-OC4H7)Zn(CH2SiMe3)].5 Conventional metalation of THF invariably initiates decomposition by ring opening,8 but in this low-polarity zincation the 5-atom ring of the sensitive α-deprotonated THF anion remains intact. However, this reaction is extremely slow (best yield was 52.7 % after 2 weeks) and requires a massive stoichiometric excess of the cyclic ether (i.e., carried out in neat THF solvent). Here we report a vastly superior methodology to the cyclic THF α-anion, mediated by a lithium aluminate base with a higher amido content than the alkyl-rich zincate reagent. An analogous reaction with the sulfur analogue, tetrahydrothiophene (THTP), is also reported.


Crosbie, Elaine, Garcia-Alvarez, Pablo, Kennedy, Alan R. ORCID logoORCID:, Klett, Jan, Mulvey, Robert E. ORCID logoORCID: and Robertson, Stuart D. ORCID logoORCID:;