Access to Atropisomerically En­riched Biaryls by the Coupling of Aryllithiums with Arynes under Control by Homochiral Oxazolines

Abstract

We report the preparation of axially stereoenriched biphenyls by the coupling of in situ generated aryllithiums and arynes using chiral oxazoline auxiliaries. The design of the aryne precursors, the choice of oxazoline and the reaction conditions were key to accessing the desired, highly substituted, atropisomerically enriched biarylic products. In one case, the two atropo‐diastereomers could be obtained in isomerically pure form by column chromatographic separation and their absolute configurations established by X‐ray crystallography. The stereoselectivity of the reaction seems to be governed by subtle parameters.

Transition‐Metal‐Free Synthesis of a Known Intermediate in the Formal Synthesis of (–)‐Steganacin

“…In both cases, no desired aldehyde was obtained after work‐up. The formation of fluorenone at the detriment of the trapping by DMF is coherent with our previous findings , . Indeed, cyclization of the biaryllithium intermediate is favored over trapping with an electrophile when the latter is either slowly reacting or not already present in the reaction medium for the in situ trapping of the forming biaryllithium.…”

“…Indeed, addition of 1 equiv. of butyllithium in THF at –78 °C to 4b ( S ,a S ) as a model in place of the desired 4a ( S ,a R ), followed by trapping with DMF after 30 min led only to the undesired fluorenone 5 in 69 % yield. When the time before the addition of DMF was reduced to 5 min we surprisingly recovered 50 % of the starting material, that is, with the iodine untouched, with 5 still formed in 39 % yield.…”

“…Therefore, we wished to perform the protodesilylation at a low temperature if possible. We again started first with the model bis(trimethylsilylated) biaryl 6 (Scheme ), which we described previously, and treated it with TFA, a known desilylating agent of electron‐rich aromatic rings . The reaction proceeded well in the presence of excess TFA at room temperature, although a long time was required to fully remove the TMS group at the 6‐position of the biaryl.…”

“…Although very moderate selectivity was achieved, we showed that the desired biaryl 4 could be produced in a satisfying yield of 67 %, given the steric bulk surrounding the newly formed tetra‐ ortho ‐substituted aryl–aryl bond. Both atropo‐diastereoisomers could be separated by column chromatography and their absolute configurations determined by X‐ray diffraction . Having created the biaryl backbone of (–)‐steganacin ( 2 ), we then wished to transform 4 into intermediate 3 without using transition metals.…”

Base-Induced Cyclisation of ortho-Substituted 2-Phenyloxazolines to Give 3-Aminobenzofurans and Related Heterocycles

“…Better selectivity for 3 was obtainedusingtheBuLi/t-BuOKmixturebut1.1equivalents As far as we are aware, the only previous examples of intramolecularbase-inducedcyclisationofacarbanionontoan oxazoline resulting in ring-opening of the latter are a single example of naphtho [2,3-b]thiophene formation upon treatment of a 1-bromo-2-naphthyloxazoline with the sodium salt of 4-chlorobenzylmercaptan, 5 and two reports in which fluorenoneproductsareformedasbyproductsintreatmentof an ortho-lithiated phenyloxazoline with an aryne. 6,7 The current process does bear a close resemblance to the Gewald reaction, 8 inwhichanortho-alkoxybenzonitrileistreatedwith base leading to a 3-aminobenzofuran. Although this process originally required a strongly electron-withdrawing substituent on the alkoxy group, more recent examples show that it also works with less stabilised anions, 9-11 including the cyclisationof2-benzyloxy-3-cyanopyridine.…”