Evaluating cis-2,6-dimethylpiperidide (cis-DMP) as a base component in lithium-mediated zincation chemistry

D.R. Armstrong, J.A. Garden, A.R. Kennedy, S.M. Leenhouts, R.E. Mulvey, P. O'Keefe, C.T. O'Hara, A. Steven

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Most recent advances in metallation chemistry have centred on the bulky secondary amide 2,2,6,6-tetramethylpiperidide (TMP) within mixed metal, often ate, compositions. However, the precursor amine TMP(H) is rather expensive so a cheaper substitute would be welcome. Thus this study was aimed towards developing cheaper non-TMP based mixed-metal bases and, as cis-2,6- dimethylpiperidide (cis-DMP) was chosen as the alternative amide, developing cis-DMP zincate chemistry which has received meagre attention compared to that of its methyl-rich counterpart TMP. A new lithium diethylzincate, [(TMEDA)LiZn(cis-DMP)Et] (TMEDA=N,N,N′,N′- tetramethylethylenediamine) has been synthesised by co-complexation of Li(cis-DMP), EtZn and TMEDA, and characterised by NMR (including DOSY) spectroscopy and X-ray crystallography, which revealed a dinuclear contact ion pair arrangement. By using N,N-diisopropylbenzamide as a test aromatic substrate, the deprotonative reactivity of [(TMEDA)LiZn(cis-DMP)Et] has been probed and contrasted with that of the known but previously uninvestigated di-tert-butylzincate, [(TMEDA)LiZn(cis-DMP)tBu]. The former was found to be the superior base (for example, producing the ortho-deuteriated product in respective yields of 78 % and 48 % following D O quenching of zincated benzamide intermediates). An 88 % yield of 2-iodo-N,N-diisopropylbenzamide was obtained on reaction of two equivalents of the diethylzincate with the benzamide followed by iodination. Comparisons are also drawn using 1,1,1,3,3,3-hexamethyldisilazide (HMDS), diisopropylamide and TMP as the amide component in the lithium amide, EtZn and TMEDA system. Under certain conditions, the cis-DMP base system was found to give improved results in comparison to HMDS and diisopropylamide (DA), and comparable results to a TMP system. Two novel complexes isolated from reactions of the di-tert-butylzincate and crystallographically characterised, namely the pre-metallation complex [{(iPr)N(Ph)Ci'O}LiZn(cis-DMP)tBu ] and the post-metallation complex [(TMEDA)Li(cis-DMP){2-[1-C(=O) N(iPr)]CH}Zn(tBu)], shed valuable light on the structures and mechanisms involved in these alkali-metal-mediated zincation reactions. Aspects of these reactions are also modelled by DFT calculations. Amide austerity: Lithium amidozincate bases replacing expensive TMP (2,2,6,6-tetramethylpiperidide) by inexpensive cis-DMP (cis-2,6- dimethylpiperidide) have been synthesised (see scheme) and utilised for the ortho-deprotonation of a benzamide substrate for comparision with their TMP and other common amido analogues.
Original languageEnglish
Pages (from-to)13492-13503
Number of pages12
JournalChemistry - A European Journal
Issue number40
Publication statusPublished - 27 Sep 2013


  • amides
  • lithium
  • metallation
  • structural elucidation
  • zincates


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