The concise synthesis and resolution of planar chiral [2.2]paracyclophane oxazolines by C–H activation

Planar chiral [2.2]paracyclophanes are resolved through the direct C–H arylation of enantiopure oxazolines, providing a convenient route to ligands and chiral materials. Preliminary results show that hydrolysis followed by decarboxylative phosphorylation leads to enantiopure [2.2]paracyclophane derivatives that are otherwise challenging to prepare.

Benzyloxazoline 8a was formed as a mixture of diastereoisomers that are separable by column chromatography, but the similarity of the R f values make resolution extremely challenging, with only the fractions at the beginning and end of a collection containing pure diastereoisomers. This led to screening a range of oxazolines. All coupled but with less satisfactory yields. The phenyloxazoline 6b appears to couple with concomitant aromatisation furnishing oxazole 9. For mono(oxazolines) 8, tert-butyl derivative 6c gave the best results in terms of resolution of planar chirality, with the diastereoisomers 8c being readily separable. 21 Next we established the scope of coupling reaction. Both the pseudo-para-(4,16)-(11a) and pseudo-ortho-(4,12)-bis(oxazolines) 11b were readily prepared from the corresponding dibromo[2.2]paracyclophanes ( Table 1). The pseudo-para isomer, 4,16-bis(4 0 -benzyloxazolin-2 0 -yl) [2.2]paracyclophane 11a, is formed as a single stereoisomer due to its symmetry. The diastereoisomers of the more useful pseudo-ortho benzylsubstituted oxazoline 11b were readily resolved, 17,20,29 but only one diastereoisomer of the tert-butyl derivative 11c could be isolated. The other diastereoisomer co-ran with the two diastereomers of the product of protodebromination (8c). The synthesis of pseudo-ortho-bis(benzyloxazoline) 11b has been performed on >1 g scale. The yields are lower but the separation easier. If a single equivalent of 2H-oxazoline 6a is used in the coupling, it is possible to isolate the bromo mono(oxazoline) 11d, but the reaction is non-selective, with a mixture of monoalong and bis(oxazoline) always formed. 16,18,30 As is frequently observed with [2.2]paracyclophane derivatives, each regioisomer behaves differently, and it is hard to predict the inuence of the substituents. 31,32 Using t-Bu 2 SPO as pre-ligand, both primary and tertiary pseudo-gem amines gave the desired oxazolines as separable diastereoisomers 11e and 11f. The normally unreactive ortho substituted [2.2]paracyclophane derivative, 4-amino-5-bromo[2.2]paracyclophane, 33 appeared to give the amino-oxazoline 11g as a pair of separable diastereomers in 34% yield, although these compounds proved to be unstable. All other amino [2.2]paracyclophanes gave unsatisfactory yields. The pseudo-ortho-amino-bromo [2.2] paracyclophane failed to couple and only furnished the product of protodebromination. On changing to Ad 2 SPO, the meta 11h and pseudo-para 11i, were synthesised as separable diastereomeric amino oxazolines in moderate to good yields while the pseudo-meta-amino-bromo [2.2]paracyclophane gave 11j as an inseparable mixture of diastereomers. It is unclear why this ligand is superior with these amino-bromo [2.2] paracyclophanes.
Nitro-substituted [2.2]paracyclophanes (pseudo-gem and pseudo-meta) are unreactive. Esters proved problematic, giving low yields (11k and 11m) and/or the product of protodebromination (12). We assume that the strongly basic conditions are incompatible with this functionality. This is supported by the fact the free acid reacts in good to moderate yields, 44% for pseudo-gem (11l) and 61% for pseudo-ortho (11n) ( Table 1).
There are numerous reports describing the utility of [2.2] paracyclophane oxazolines. They have been used as preligands, 16,[18][19][20]29 or have directed further functionalisation of the [2.2]paracyclophane by either bromination 16,23 or metalation. 19,21 We believe straightforward elaboration of the amine or acid functionality will deliver modular pre-ligands, but here we want to increase the versatility of the oxazoline moiety and present preliminary results on the hydrolysis and decarboxylative phosphorylation of the oxazolines.
Oxazolines are robust, and hydrolysis is not straightforward. The hydrolysis of 11e by heating to reux in 6 M HCl has been reported to give 13b in good yield (Table 2), 18 and these conditions worked for mono(benzyloxazoline) 8a but failed to hydrolyse the mono(tert-butyloxazoline) 8c or the bis(oxazoline) 11b. More forcing conditions using concentrated sulfuric acid in dioxane at 110 C lead to the clean hydrolysis of mono(oxazolines) while the pseudo-ortho bis(oxazoline) gives a mixture of the 4-acid-12oxazoline 11n and the desired 4,12-diacid 13c. Fortunately, the products are easily separated based on solubility and recycling 11n permits good overall yields of 13c to be achieved. No sign of racemisation can be detected by optical rotation. While the conditions are harsh, the rapid synthesis of the oxazolines with concomitant resolution still make this methodology attractive if conducted early in a synthetic sequence.
It is possible to subject the enantiomerically enriched 4carboxylic acid 13a to a decarboxylative phosphorylation to give the phosphine oxide 14 in 8-20% (along with 50% unreacted starting material with no erosion of enantiopurity (Scheme 3). [35][36][37] So far, we have been unable to react the pseudoortho-diacid under the same conditions. Although the preliminary results are low yielding, they demonstrate that it is possible to isolate enantiomerically enriched phosphine oxide in just four steps. Only our own sulfoxide chemistry 38,39 is as efficient and that methodology was limited by the need for a sulfoxidelithium exchange with tert-butyllithium.
[2.2]Paracyclophane offers a useful planar chiral skeleton but its widespread adoption has been frustrated by a lack of simple methods to resolve the planar chirality. In this paper, we have shown how oxazolines can be coupled to bromoderivatives to give separable diastereomers. The methodology permits a range of disubstituted [2.2]paracyclophanes to be rapidly prepared in enantiomerically pure form. We report the rst example of a decarboxylative coupling on [2.2]paracyclophane. Optimisation of the decarboxylative coupling offers an exciting new route to enantiomerically enriched planar chiral molecules that are challenging to synthesise by conventional methods. We intend to extend the utility of this reaction to other derivatives, and will publish these studies in due course. Simpler, more rapid access to enantiomerically pure [2.2]paracyclophane derivatives will facilitate their wider use in catalysts, bioactive compounds, and materials.

Author contributions
ST and MNM contributed equally to this research.

Conflicts of interest
There are no conicts to declare.