Incremental Solvation Precedes Ion‐Pair Separation in Enantiomerization of a Cyano‐Stabilized Grignard Reagent

Abstract

[a] Dedicated to Professor K. Barry Sharpless on the occasion of his 70th birthday Configurationally stable enantioenriched organolithium compounds are important in asymmetric synthesis.[1] Studies of the enantiomerization pathways of these compounds are useful for improving the stereochemical outcome of these reactions, and provide insight into the structure and dynamics of these compounds.[1a, f, 2] The composition of the organic fragment, [1a, f, 2a, d] the presence of additives, [2d, 3] and the identity of the solvent [2d, 4] are all known to affect configurational stability. In contrast, few such studies have been reported for enantioenriched organomagnesium compounds, perhaps reflecting the relative paucity of these reagents.[5] Herein we report Eyring analyses and reaction order studies of the racemization of enantioenriched Grignard reagent 2 in ethereal solvents. Enantiomerization rates increase in the order Et 2 O < 2-methylTHF < THF. A highly negative activation entropy for enantiomerization ((À49 AE 4) eu) is seen under conditions where reaction is zero-order in [Et 2 O] and first-order in [Mg]. These results are consistent with an ion-pair separation enantiomerization mechanism wherein association of solvent precedes rupture of the Mg À C bond. To our knowledge this is the first experimental determination of the timing of incremental solvation and ion-pair separation for a Group I or II organometallic reagent.We previously reported [5h] that enantioenriched cyano-stabilized Grignard reagent 2 could be prepared by Mg/Br exchange [6] of enantiopure a-bromonitrile (S)-1 with iPrMgCl (Scheme 1). The overall transformation of (S)-1 to [D 1 ]-3 was shown to favor retention, and measurements of the e.r. of [D 1 ]-3 with increasing delay time t demonstrated that 2 possessed a racemization half life (t 1/2 A C H T U N G T R E N N U N G (rac)) of 11.4 h in Et 2 O at 173 K. The extrapolated e.r. at t = 0 for 2 from these experiments was 91:9, suggesting that Mg/Br exchange was not perfectly retentive.To explore the role of solvent in the enantiomerization process, we reinvestigated this reaction in Et 2 O, 2-methyltetrahydrofuran (2-MeTHF), and THF, at several temperatures. A key feature of our reinvestigation was the use of a precooled CH 3 OD quench in place of room-temperature D 2 O.[7] Delay times t varied from 60 to 3600 s and > 95 % recovery of [D 1 ]-3 (> 98 % deuterium incorporation) was obtained after workup even at the shortest time points (60 s) at 175 K. First-order rate constants for enantiomerization of 2 (k enant ) derive from slopes (À2k enant ) of the plots of ln-versus delay time t (Figure 1).[8]

C- and N-Metalated Nitriles: The Relationship between Structure and Selectivity

“…38 Pioneering deprotonations of cyclopropanecarbonitrile 47a 39 demonstrate that the free carbanion 48a has a short, discrete existence (Scheme 8). Performing the deprotonation in deuterated methanol provides an internal trap that minimizes equilibration (48a → 48b → 50), allowing 40 Intricate mechanistic experiments suggested that enantiomerization occurs through a solvent-dependent 41 ion pair separation and inversion mechanism (51 → 48) 42 rather than through a conducted-tour equilibration. 18 Armed with the knowledge that magnesiated nitriles epimerize more slowly, 43 research has focused on trapping chiral magnesiated nitriles 44 with adjacent coordinating groups.…”

“…Metal–halogen exchange established an 11 kcal mol –1 inversion barrier for epimerization of C-magnesiated nitrile 51 , which translates into a half-life for racemization of 11.4 h at −100 °C for the magnesiated nitrile compared with less than 12 s for the corresponding lithiated nitrile . Intricate mechanistic experiments suggested that enantiomerization occurs through a solvent-dependent ion pair separation and inversion mechanism ( 51 → 48 ) rather than through a conducted-tour equilibration …”

Stereochemical Inversion of a Cyano-Stabilized Grignard Reagent: Remarkable Effects of the Ethereal Solvent Structure and Concentration

“…By monitoring the enantiomer ratios (er’s) of the deuteration product d 1 - 3a , we demonstrated that Mg/Br exchange of enantiopure bromide ( S )- 2a with i -PrMgCl was more highly retentive in Et 2 O than in 2-methyltetrahydrofuran (2-MeTHF) or THF. In addition, the enantiomerization rate constant ( k enant ) of ( S )- 1a was much smaller in Et 2 O than in the other solvents (Scheme ) …”

Chemoselective Alkylations with N- and C-Metalated Nitriles

“…The preference of C -magnesiated nitriles for oxygenated electrophiles does not preclude alkylations with alkyl halides. Magnesiated nitriles are configurationally labile and readily equilibrate from C -magnesiated to N -magnesiated nitriles through conducted tour or ion exchange mechanisms . Consistent with this mechanistic suggestion, for alkylations of the lithiated nitrile 2a with mixtures of benzyl bromide and methyl cyanoformate, increasing the ratio of methyl cyanoformate from 1:1 to 2:1 through 5:1 to 10:1 results in higher ratios of the ester 8a relative to the benzyl nitrile 6a (3.1:1, 5.0:1, and 10.1:1, respectively).…”