Evaluating cis‐2,6‐Dimethylpiperidide (cis‐DMP) as a Base Component in Lithium‐Mediated Zincation Chemistry

Abstract

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)Et2] (TMEDA=N,N,N′,N′-tetramethylethylenediamine) has been synthesised by co-complexation of Li(cis-DMP), Et2Zn 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)Et2] has been probed and contrasted with that of the known but previously uninvestigated di-tert-butylzincate, [(TMEDA)LiZn(cis-DMP)tBu2]. The former was found to be the superior base (for example, producing the ortho-deuteriated product in respective yields of 78 % and 48 % following D2O 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, Et2Zn 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)2N(Ph)C=O}LiZn(cis-DMP)tBu2] and the post-metallation complex [(TMEDA)Li(cis-DMP){2-[1-C(=O)N(iPr)2]C6H4}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.

Sodium Diisopropylamide: Aggregation, Solvation, and Stability

“…DOSY is increasingly popular, 15,16,17 and our results could be considered supportive. That said, however, we remain cautious owing to significant (up to 30%) temperature-dependent changes in measured molecular weights that do not appear to derive from changes in structure.…”

“…Similar temperature dependencies have been noted by others. 16,17 We have no evidence, however, that the reduced value at −80 °C is based on a structural change: low temperature promotes rather than retards solvation owing to negative enthalpy. Also, the solubility of NaDA in DMEA is nearly temperature-independent.…”

“…Nonetheless, we applied several experimental methods to determine the solvation as follows. Proton diffusion-ordered NMR spectroscopy ( 1 H-DOSY), first applied to organolithium aggregates by Williard, 15 is now proliferating within the field 16 and has been applied to organosodiums. 17 Underlying assumptions about molecular shape and influence on the diffusion constant have always left us uneasy, however.…”

Structural Effects in Lithiocuprate Chemistry: The Elucidation of Reactive Pentametallic Complexes

“…Notably, DMPH also retails at a fraction of the cost of TMPH. [ 14 ] In the present case, DMPLi was added to CuX in the presence of Lewis base (bulk or 1 or 2 equiv Et 2 O with respect to Cu). Attempts to isolate a product when X=CN are yet to bear fruit.…”

“…[ 6 ] In both cases, high conversion is achieved using bases made with DMPH, suggesting major cost benefits. [ 14 ] To improve our mechanistic understanding, we have now initiated a detailed study of the solution behaviour of these adducts. [ 18 ] We are also seeking to use various amines to probe the relationship between ligand bulk and structure type.…”