Thermal epimerization of diastereomeric Grignard reagents

Beckmann, Jens; Schütrumpf, Alexandra

doi:10.1039/b819178f

Cited by 6 publications

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“…Reported data are faintly conflicting b Bornylmagnesium chloride forms as a kinetic endo / exo 67:33 mixture but changes to 96:4 upon heating. , c Menthylmagnesium compounds slowly epimerize at rt (this work). d Hoffmann’s open-chain chiral Grignard reagent racemizes quickly at rt …”

Section: Resultsmentioning

confidence: 92%

Stereochemistry of the Menthyl Grignard Reagent: Generation, Composition, Dynamics, and Reactions with Electrophiles

et al. 2018

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Menthyl Grignard reagent 1 from either menthyl chloride (2) or neomenthyl chloride (3) consists of menthylmagnesium chloride (1a), neomenthylmagnesium chloride (1b), trans-p-menthane (4), 2-menthene (8), 3-menthene (9), and Wurtz coupling products including symmetrical bimenthyl 13. The diastereomeric ratio 1a/1b was determined in situ by 13 C NMR or after D 2 O quenching by 2 H NMR analysis. Hydrolysis of the C−Mg bond proceeds with retention of configuration at C-1. The kinetic ratio 1a/1b from Grignard reagent generation (dr 59:41 at 50 °C in THF) is close to the thermodynamic ratio (56:44 at 50 °C in THF). Carboxylation of 1 at −78 °C separates diastereomers 1a/b to give the anion of menthanecarboxylic acid (19) from 1a, which combines with unreactive 1b to give neomenthylmagnesium menthanecarboxylate (1b I ). The kinetics of epimerization for the menthyl/neomenthylmagnesium system was analyzed (ΔH ⧧ = 98.5 kJ/mol, ΔS ⧧ = −113 J/mol•K for 1b I → 1a I ). Reactions of 1 with phosphorus electrophiles proceed stereoconvergently at C-1 of 1a/b to give predominantly menthyl-configured substitution products: PCl 3 and 2 equiv of 1 give Men 2 PCl (6), which hydrolyzes to dimenthylphosphine P-oxide (7), whereas Ph 2 PCl with 1 equiv of 1 gave Pmenthyldiphenylphosphine oxide (27) after workup in air.

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Section: Resultsmentioning

confidence: 92%

Stereochemistry of the Menthyl Grignard Reagent: Generation, Composition, Dynamics, and Reactions with Electrophiles

et al. 2018

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“…In this case, the diastereoselectivity (92 % and 88 % de) even exceeds that of the Grignard formation (34 % and 60 % de). [4] No definitive explanation can be given for this exceptionally high diastereoselectivity at this stage. However, the different diastereoselectivities may be correlated with the LUMO levels [2] of the chlorophosphanes calculated at the MP2/6-311+ g(2d,p) level of theory, [11] which increases in the order Ph 2 PCl (1.5508 eV) Ͻ PCl 3 (1.5511 eV) Ͻ (Et 2 N) 2 -PCl (1.5984 eV), respectively.…”

Section: Discussionmentioning

confidence: 92%

“…The same observation was made for the formation of the fenchyl Grignard reagent. [4] Apparently, the reactions involve the same radical intermediate, namely the fenchyl radical, which has a strong bias on the formation of exo products.…”

Section: Discussionmentioning

confidence: 99%

“…[2] We turned our attention to diastereomeric Grignard reagents prepared by the direct method from Mg and sec-alkyl chlorides derived from naturally occurring inexpensive monoterpenes, such as menthol, [3] borneol and fenchol. [4] These Grignard reagents have three chiral centers and consist of configurationally stable mixtures of diastereomers, which differ only in the configuration of the α-carbon atom. Consistent with the SET mechanism, the ratio of the diastereomers is entirely independent of the initial configuration of the α-carbon atom of the alkyl chloride.…”

Section: Introductionmentioning

confidence: 99%

“…The diastereomeric composition of the Grignard reagents was unambiguously determined by reaction with the soft model electrophile triphenyltin chloride giving rise the formation of air-stable diastereomeric mixtures of terpenoid alkyltriphenylstannanes that were qualitatively and quantitatively assessed by 119 Sn, 13 C and 1 H NMR spectroscopy. [4] We have now studied the reaction of the (epimerized) bornyl and fenchyl Grignard reagents with the selected chlorophosphanes, Ph 2 PCl, PCl 3 and (Et 2 N) 2 PCl. These reactions provided diastereomeric mixtures of bornylphosphanes and isobornylphosphanes as well as α-fenchylphosphanes and β-fenchylphosphanes.…”

Section: Introductionmentioning

confidence: 99%

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Reactions of the Bornyl and Fenchyl Grignard Reagent with Chlorophosphanes – Diastereoselectivity and Mechanistic Implications

Beckmann

Schütrumpf

2009

Eur J Org Chem

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The reactions of the bornyl and fenchyl Grignard reagent with the chlorophosphanes Ph2PCl, PCl3 and (Et2N)2PCl, respectively, were studied by multinuclear NMR spectroscopy. The diastereoselectivity was found to be independent of the diastereomeric composition of the bornyl andfenchyl Grignard reagent (e.g., the endo/exo ratio), but dependent on the chlorophosphanes used. The results are consistent with a reaction mechanism that involves SET processes and radical intermediates. No or little diastereoselectivity was observed for the reactions involving Ph2PCl and PCl3. The reactions of the bornyl and fenchyl Grignard reagent with (Et2N)2PCl provided bornylP(NEt2)2 (4a) and β‐fenchylP(NEt2)2 (10b) with high diastereoselectivity (of 92 % and 88 % de). The novel chiral phosphane oxides bornylPh2PO (2a), isobornylPh2PO (2b), α‐fenchylPh2PO (8a) and β‐fenchylPh2PO (8b), phosphinic acids bornylP(O)(H)(OH) (5a) and β‐fenchylP(O)(H)(OH) (11b) and phosphonic acids bornylP(O)(OH)2 (6a) and β‐fenchylP(O)(OH)2 (12b) were isolated as colorless crystals. The molecular structures of 2b, 8a, 8b, 6a and 12b were determined by X‐ray crystallography.

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

Gao

Carlier

2011

Chemistry A European J

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[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]

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Thermal epimerization of diastereomeric Grignard reagents

Abstract: Thermal epimerization is the key to changing the endo-to-exo ratio of the diastereomeric bornyl and fenchyl Grignard reagents from 67:33 to 96:4 and from 20:80 to 80:20, respectively.

Cited by 6 publications

References 5 publications

Stereochemistry of the Menthyl Grignard Reagent: Generation, Composition, Dynamics, and Reactions with Electrophiles

Stereochemistry of the Menthyl Grignard Reagent: Generation, Composition, Dynamics, and Reactions with Electrophiles

Reactions of the Bornyl and Fenchyl Grignard Reagent with Chlorophosphanes – Diastereoselectivity and Mechanistic Implications

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

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