Chiral Organolithium Complexes:  The Structure of β-Lithiated β-Phenylcarboxamides and the Mechanism of Asymmetric Substitution in the Presence of (−)-Sparteine

Abstract

Investigation of the structure and reactivity of β-lithiated β-phenylcarboxamides is reported. NMR spectroscopic investigations of β-lithiated amides 15 and 24 establish that the benzylic lithium is complexed by the nitrogen of the amide. The β-lithiated N-methyl amide 15 forms a complex with (−)-sparteine (4) which undergoes electrophilic substitution to provide enantioenriched products. The β-lithiated N-isopropyl amide 24 does not form a complex with 4, so there is no asymmetric induction. The enantioselectivity of the reaction is shown to arise by the pathway of asymmetric substitution in which asymmetry is induced in a postdeprotonation step. Asymmetric induction in this lithiation−substitution sequence is suggested to occur via a dynamic thermodynamic resolution.

Beyond Thermodynamic Acidity: A Perspective on the Complex‐Induced Proximity Effect (CIPE) in Deprotonation Reactions

“…An NMR spectroscopic study of the structure of 13 C-, 6 Li-, and 15 N-labeled 22·(À)-sparteine established that the nitrogen atom of the amide is associated with the lithium center bound to the benzylic carbon atom. [39] The crystal structure of the a-lithiated benzyl amide 23 shows both intramolecular and intermolecular ligand binding. [40] Studies of ground-state structures also show agostic interactions between CÀH bonds and lithium atoms, which may precede proton transfer and can be interpreted to provide support for CIPE.…”

Highly Enantioselective (−)-Sparteine-Mediated Lateral Metalation-Functionalization of Remote Silyl Protected ortho-Ethyl N,N-Dialkyl Aryl O-Carbamates

“…48 Results for the reaction path of all substrates examined (5,6,20) are similar, and thus only one (20) is discussed in detail using the solvated model. In order to convert N,N-dialkyl aryl O-carbamates into synthetically useful phenols following benzylic functionalization, several methods were tested.…”

“…16 Subsequent to the initial observations of Nozaki 1 and the seminal studies of Hoppe 3 and Beak,4 (-)-sparteine-mediated benzylic metalation has been investigated on several types of derivatives 1-4 (Scheme 1), which take advantage of an α-heteroatom 1a-f, 17 an orthoheteroatom 2, 18 a styryl α-amino moiety 3, 19 a β-heteroatom 4 20 Stimulated by these findings, we had previously investigated the (-)-sparteine-induced, highly enantioselective preparation of planar chiral ferrocenes and their application in an asymmetric alkylation and Pd(0)-catalyzed allylic substitution. 22 The original studies of Clark 23 To determine the influence of solvent, the N,N-dialkyl aryl O-carbamates 5 and 6 were metalated under the optimized conditions in single and mixed solvent systems and the resulting benzyllithium species were quenched with TMSCl or dimethyl disulfide (MeSSMe) to afford compounds 11a and 12b and 11b and 13a respectively (Table 1).…”

“…phenyl diisopropylcarbamate(20): t-BuLi(19.5 mL, 18.7 mmol, 0.96M solution in pentane) was slowly added to a stirred solution of 3-(trimethylsilyl)phenyl diisopropylcarbamate(2.51 g, 8.56 mmol) and TMEDA(2.18 g, 18.74 mmol) in THF (40 mL) at -78°C. The bright yellow solution was kept at -78°C for 1 h, then iodoethane (3.99 g, 25.6 mmol) was added dropwise at -78°C.…”

Asymmetric Deprotonation with Alkyllithium–(−)‐Sparteine

“…The intermediates are not configurationally stable, but at low temperature one epimer 262 or epi-262 dominates due to the higher thermodynamic stability. Consequently, Beak and coworkers propose on the basis of a detailed mechanistic investigation the pathway of dynamic thermodynamic resolution 196 (11) to form the benzyllithium derivative 265 (equation 64) 197 . The reaction with different electrophiles (Me 3 SiCl, Bu 3 SnCl, alkyl halides, cyclohexanone, benzaldehyde) provides the (S)-enantiomers of the phenylethylamides 266 with good excesses.…”