Elsevier

Tetrahedron

Volume 72, Issue 34, 25 August 2016, Pages 5208-5220
Tetrahedron

Atropo-diastereoselective coupling of aryllithiums and arynes — variations around the chiral auxiliary

https://doi.org/10.1016/j.tet.2016.01.047Get rights and content

Abstract

The atropo-selective coupling of in situ generated arynes and aryllithiums bearing various chiral auxiliaries ortho to lithium (tert-butylsulfoxide, para-tolylsulfoxide, tartrate-derived chiral diethers and oxazolines) is described. Chiral oxazolines showed the best results in terms of yields of coupling products. Different reaction parameters like the nature of the aryne precursor, the oxazoline, the alkyllithium base or the solvent revealed to be crucial for obtaining good yields and for diastereoselection.

Introduction

Among the methods allowing access to the biphenyl backbone, the addition of an aromatic carbanion onto a 1,2-didehydroarene, i.e., an ortho-aryne, was postulated by Gilman in the late 1950s in the reaction of ortho-dihalobenzenes with butyllithium.1 However, this halogen/lithium interconversion-based method remained rather dormant for several decades while the magnesium-based counterpart was intensively studied by Hart.2 We started reinvestigating the former in 2001 and then extended its scope to access various biaryls, which could be derivatized to prepare phosphorous ligands, and we clarified the mechanism of the reaction (Scheme 1).3 This ‘ARYNE coupling’ is actually a chain reaction, proceeding via sequential halogen/lithium exchanges, and finally yields 2-halobiphenyls that can be functionalized further. Once having developed efficient conditions for the ARYNE coupling, we became interested in its application to the preparation of axially chiral biaryls. Indeed, the synthesis of axially stereoenriched biaryls remains an active research field motivated by their presence in natural products or their use as biologically active compounds, chiral ligands for catalysis, chiral auxiliaries for asymmetric synthesis or optically active organic materials. The most widespread strategies are the resolution of pre-constructed biaryls and the atropo-selective coupling of two aromatic partners.4 We first tackled the resolution strategy by taking advantage of a specificity of the ARYNE coupling, namely the regeneration of a carbon-exchangeable halogen bond in position 2 of the biaryl product, to introduce a chiral sulfinyl auxiliary enabling desymmetrization or deracemization of the biaryl, separation of atropo-diastereomers, and lastly functionalization by sulfoxide/lithium exchange.3g We then investigated the atropo-diastereoselective ARYNE coupling, where a coupling partner bears a chiral auxiliary prior to the coupling, so as to yield atropo-diastereomers of the desired biaryl.3, 5 We wish, in the present paper, to describe our efforts towards this aim.

Section snippets

Results and discussion

In the development of the atropo-diastereoselective version of the ARYNE coupling, the choice of the chiral auxiliary and its location onto the coupling partners were critical. First, the auxiliary should be able to bind to lithium, in order to produce more rigid transition states and, consequently, lead to higher stereoselectivity. Therefore, an oxygen- and/or nitrogen-bearing auxiliary was needed. Second, to avoid regioselectivity issues during the addition of the aryllithium nucleophile onto

Conclusion

The atropo-selective coupling of in situ generated arynes and aryllithiums bearing various chiral auxiliaries ortho to lithium was performed. tert-Butyl sulfoxides gave low to high yields of the coupling product with variable diastereoselectivity. para-Tolyl sulfoxides, on the other hand, were unable to produce the desired biaryls, mainly because of a lack of reactivity of the 2-lithiophenyl p-tolyl sulfoxide intermediates towards halogen/lithium exchange and/or trapping by the aryne; yet they

General methods

Starting materials, if commercially available, were purchased and used as received after checking their purity. When known compounds had to be prepared according to literature procedures, pertinent references are given. Air and moisture-sensitive materials were stored in Schlenk tubes under argon. Et2O and THF were dried by distillation over sodium/benzophenone after the characteristic dark blue or purple color of mono- or disodium diphenyl ketyl had been found to persist. CH2Cl2 was dried over

Acknowledgements

This work was supported by the CNRS (Centre National de la Recherche Scientifique, France). B. Y. is very grateful to the Malian government for a doctoral grant. A.B.B. thanks the ‘Ministère de l’Education Nationale et de la Recherche’ (France) for an MENRT Ph.D. grant. D. A., A. P. and F. L. thank the French ‘Agence Nationale pour la Recherche’ (ANR-14-CE06-0003-01, ChirNoCat) for financial support.

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