Elsevier

Tetrahedron: Asymmetry

Volume 20, Issue 21, 4 November 2009, Pages 2497-2503
Tetrahedron: Asymmetry

Reaction prospecting by 31P NMR: enantioselective rhodium-DuPhos catalysed addition of ZnMe2 to diphenylphosphinoylimines

https://doi.org/10.1016/j.tetasy.2009.09.020Get rights and content

Abstract

Chiral shift 31P NMR spectroscopy allows the identification of ligand leads in asymmetric catalyst systems for ZnMe2 addition to ArCHdouble bondNP(O)Ph2. Subsequent GC-based optimisation shows [RhCl(CH2double bondCH2)2]2 and (R,R)-MeDuPhos to be the optimal pre-catalyst combination (product in 78–93% ee). Transmetallation of [(MeDuPhos)Rh{N(P(O)Ph2–CHMeAr}] with ZnMe2 appears to be the rate limiting step of the catalytic cycle as competing coordination by the imine starting material leads to Ph2P(O)NHCH2Ar via MVP hydrogen-transfer. This limitation can largely be overcome by the slow addition of the imine.

Introduction

Convenience and technical simplicity are defining goals in contemporary organic methodology. Recently, we experienced a need for chiral 2-arylethylamines 1 (Scheme 1) for use in ligand synthesis1 and sought to attain a straightforward method for their production from precursor aldimines 3 via protected 2. Our criteria for such a preparation were: (i) that the N-protecting group must engender crystallinity in the products, but be easily removed (ii) that any chiral ligand and metal additives used in preparing 2 be readily commercially available (iii) that the reaction proceed rapidly and (iv) that any screening procedures leading to the enantioselective catalyst for production of 2 should be readily applicable to high throughput screening and not complicated by the presence of impurities. Recently several excellent processes for the preparation of precursors to 1 have appeared in the literature,2, 3 but these often raise issues when compared against harsh criteria (i)–(iv) above. Hayashi3b has described active and selective diene-ligated rhodium catalysts. However in this case, the use of aldimine 3a (PG = Ts) is required. The removal of such tosyl protecting groups sometimes can be problematic. Charette3c has described Cu(OTf)2/DuPhos-monooxide approaches using 3b [PG = P(O)Ph2] in up to 97% ee but the reaction is relatively slow (48 h). In our hands, alkylations employing 3b were also prone to producing significant amounts (∼10%) of fluorescent co-eluting by-products in initial trials that invalidated or slowed down chiral HPLC high throughput screenings when using 3b. We thought that we might be able to utilize the power of 31P NMR spectroscopy to overcome these issues in catalyst discovery.

Section snippets

Synthesis of aldimines 3b and catalyst discovery by 31P NMR spectroscopy

In our hands the starting aryl imines 3b were best prepared using the detailed Ph2P(O)NH2/TiCl4/ArCHO procedure provided by Scheidt.4 We were only able to improve on this procedure in two ways. Firstly, the isolated yields of the somewhat hydrolytically labile imines 3b are improved by prompt chromatography in EtOAc/CH2Cl2 compared to just EtOAc, as recommended, due to solubility issues with 3b. Secondly, the relatively commercially expensive Ph2P(O)NH2 was prepared from inexpensive Ph2P(O)Cl

Conclusion

The use of 31P NMR enabled us to realise our goal of identifying a useful system for the preparation of 2-arylethyl amines 1 through the addition of methyl organometallics to imines 3b. Complications were observed due to competing chemoselectivity (reduction) issues and the apparent complex dependency of the enantiofacial selectivity as a function the substituent pattern within the aryl group. Fortunately, the phosphamides 2b are all crystalline compounds and enantioselective enrichment to >99%

General

All experiments were carried out under an argon atmosphere using standard Schlenk techniques. Solvents were dried prior to use: THF and diethyl ether were distilled from sodium-benzophenone ketyl and dichloromethane from calcium hydride. Proton, 13C and 31P NMR spectra were recorded on Bruker DPX400, Bruker AV400 and Bruker AV(III)400 spectrometers using Me4Si or residual CHCl3 as an internal reference. Infrared spectra were recorded on a Bruker Tensor 27 machine. Mass spectra were recorded

Acknowledgements

Two of us (R.C., S.E.H.) are grateful to ChiroTech Technology Ltd for support of Ph.D. studentships. We also thank this organisation for generous gifts of chiral ligands and complexes. Helpful input from the COST D40 Programme on ‘Innovative Catalysis’ and from the UK Government (EPSRC grant EP/F033478/1) is acknowledged by S.W.

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