New avenues in the directed deprotometallation of aromatics: recent advances in directed cupration

Abstract

Recent advances in the selective deprotometallation of aromatic reagents using alkali metal cuprates are reported. The ability of these synergic bases to effect deprotonation under the influence of a directing group is explored in the context of achieving new and more efficient organic transformations whilst encouraging greater ancillary group tolerance by the base. Developments in our understanding of the structural chemistry of alkali metal cuprates are reported, with both Gilman cuprates of the type R2CuLi and Lipshutz and related cuprates of the type R2Cu(X)Li2 (X = inorganic anion) elucidated and rationalised in terms of ligand sterics. The generation of new types of cuprate motif are introduced through the development of adducts between different classes of cuprate. The use of DFT methods to interrogate the mechanistic pathways towards deprotonative metallation is described. Theoretical modelling of in situ rearrangements undergone by the cuprate base are discussed, with a view to understanding the relationship between R2CuLi and R2Cu(X)Li2, their interconversion and the implications of this for cuprate reactivity. The advent of a new class of adduct between different cuprate types is developed and interpreted in terms of the options for expelling LiX from R2Cu(X)Li2. Applications in the field of medicinal chemistry and (hetero)arene derivatization are explored.

Extending motifs in lithiocuprate chemistry: unexpected structural diversity in thiocyanate complexes

“…S5 †). However, the suggestion from 7 Li NMR spectroscopy that omitting Lewis base avoided contamination of the product with minor impurities 23 led us to undertake further re-characterization, obtaining a simple 13 C NMR spectrum of the Gilman cuprate (see below) which served to aid our interpretation of the more complex behaviour of 9-11 in solution.…”

“…1 H NMR spectroscopy (500 MHz, C 6 D 6 ) δ 3.28 (q, J = 7 Hz, 8H, Et 2 O), 1.89-1.76 (m, 4H, TMP-4), 1.66-1.61 (m, 8H, TMP-3,5), 1.60 (s, 24H, TMP-Me), 1.59-1.57 (m, 4H, TMP-4), 1.56 (s, 24H, TMP-Me) 1.14-1.06 (m, 20H, Et 2 O + TMP-3,5), 1.06 (s, 7H, TMPH-Me), 0.32 (br, s, 0.44H, TMPH-NH). 13 Synthesis and characterization of (TMP) 2 Cu(SCN)Li 2 (THP) 11. A stirred solution of TMPH (0.68 mL, 4 mmol) and THP (0.17 mL, 2 mmol) in hexane/toluene (4 mL/2 mL) at −78°C was treated with n BuLi (2.5 mL, 1.6 M in hexanes, 4 mmol).…”

Deprotonative Coupling of Pyridines with Aldehydes Catalyzed by an HMDS-Amide Base Generated <i>in Situ</i>

“…1a, lower scheme). 6,7,[11][12][13][14][15][16][17][18][19][20][21][22][23] However, the preparation of these reagents requires the use of stoichiometric amounts of several chemical reagents. Hence, further development of an efficient protocol to perform this transformation is still imperative in organic chemistry.…”

Azine and Diazine Functionalization Using 2,2,6,6-Tetramethylpiperidino-Based Lithium–Metal Combinations: Application to the Synthesis of 5,9-Disubstituted Pyrido[3′,2′:4,5]pyrrolo[1,2-c]pyrimidines

“…Because of our interest in the synthesis of diaryl ketones by deprotocupration-aroylation, 5 we decided to evaluate the reactivity of these ketones toward different 4-metalated 2-substituted pyrimidines in order to reach different triaryl methanols. Thus, the required diaryl ketones were prepared from azines or diazines as reported previously.…”

“…Thus, the required diaryl ketones were prepared from azines or diazines as reported previously. 5 The latter were deprotocuprated at room temperature in tetrahydrofuran (THF) containing N,N,N′,N′-tetramethylethylenediamine (TMEDA) by using (TMP) 2 CuLi·LiCl (TMP = 2,2,6,6-tet- …”