An Experimental and Computational Study of Stereoselectivity and Reactivity in Lewis Acid Promoted Lithiation-Substitution of Tertiary Amines

Abstract

Reaction of BF3 coordinated N-ethylpyrrolidine with benzophenone, using a preformed complex of s-BuLi and (−)-sparteine for lithiation at −78 °C, affords enantio-enriched R-product (er 85:15). With a warm−cool cycle (−78° → 0°, 2 h, → −78°) prior to electrophile addition the enantioselectivity is reversed. Similarly, in the reaction of BF3-indolizidine complex syn substitution (dr 97:3) occurs but with a warm−cool cycle the syn−anti ratio gets changed to 41:59. These results indicate initial syn lithiation and formation of excess of the anti intermediate on equilibration. DFT calculations at the B3LYP/6-31+G* level show the syn intermediate to be stable in the gas phase, but with the solvent continuum treatment the relative stability shifts toward the anti arrangement and it become more stable in highly polar solvents. These computations also reveal a close contact between Li and boranato fluorine, and its implications for superior effectiveness of BF3 in promoting lithiation of amines are discussed.

Asymmetric Lithiation of Boron Trifluoride‐Activated Aminoferrocenes: An Experimental and Computational Investigation

“…The enantiomeric ratio of iodide 25c was determined by conversion to acetate 26 under the same conditions used previously to prepare 23. An interesting aspect of the preceding lithiations was the lack of reactivity of the pyrrolidine ring, [8] which may be attributed to the greater acidity of Cp hydrogens versus the a-methylene hydrogens in the heterocycle.…”

“…[1] Used originally as a means to induce deprotonation at the 2-position of pyridines (1, Figure 1), [2] the majority of studies in this field have focused on lithiation of formally sp 3 -hybridized carbon atoms a to nitrogen in cyclic amines such as tetrahydroisoquinolines [3,4] (2), Troegers base [5] (3), isoindolines [6] (4), aziridines [7] (5), pyrrolidines [3] (6) and indolizidines [8] (7). For several of these substrates (4-6), lithiation of prochiral a-methylene groups with alkyllithiums in the presence of the chiral diamine (À)-sparteine gives enantiomerically enriched products after electrophile quench.…”

“…For instance, (À)-sparteine-mediated lithiation-substitution of isoindolines [6] gives products ranging from 78:22-94:6 er (56-88% ee) via intermediate 4. Under similar conditions, enantiomerically enriched carbanions 5 [9] and 6 [8] are generated in 85:15-86:14 er (70-72% ee), determined as the benzophenone adducts (28-78% yield). In the latter cases, the a-carbanions have been shown to be configurationally stable at À78 8C, [8,9] implying that the deprotonation step is enantiodetermining.…”

“…Under similar conditions, enantiomerically enriched carbanions 5 [9] and 6 [8] are generated in 85:15-86:14 er (70-72% ee), determined as the benzophenone adducts (28-78% yield). In the latter cases, the a-carbanions have been shown to be configurationally stable at À78 8C, [8,9] implying that the deprotonation step is enantiodetermining. [10] Kessar and co-workers demonstrated in 2008 that aniline-BF 3 complexes undergo ortho-lithiation [11] of sp 2 -hydridized carbon at À78 8C (8), a much lower temperature than what is required to effect deprotonation of the free anilines [12] (e.g., n-BuLi, hexane, reflux).…”

A Study of BF3‐Promoted ortho Lithiation of Anilines and DFT Calculations on the Role of Fluorine–Lithium Interactions

“…This relatively recent methodology has been shown to be useful for lithiation of weakly acidic CÀ-H centers a to the heteroatoms of many aliphatic tertiary amines and phosphines (5!6!7!8). [3] Lewis acid activation of alkyl lithium reactions with a variety of other heteroatomcontaining substrates is also well documented; [4] for example, the 1,2-additions to imines, oximes, carbonyl compounds, and the cleavage of acetals, epoxides, and unstrained cyclic ethers. The effect of the Lewis acid is often evidenced by the improved reaction rates or changes in the chemo-, regio-, or stereoselectivities.…”