Enantioselective synthesis of atropisomeric indoles via iron catalysed oxidative cross-coupling

Abstract

Heterobiaryl compounds that exhibit axial chirality are of increasing value and interest across several fields, but direct oxidative methods for their enantioselective synthesis are elusive. Here we disclose that an iron catalyst in the presence of a chiral PyBOX ligand and an oxidant enables direct coupling between naphthols and indoles to yield atropisomeric heterobiaryl compounds with high levels of enantioselectivity. The reaction exhibits remarkable chemoselectivity and exclusively yields cross-coupled products without competing homocoupling. Mechanistic investigations enable us to postulate that the reaction proceeds through selective formation of an indole radical which is trapped by a chiral iron naphthoate in a radical-anion type coupling process. We envision that this simple, cheap, and sustainable catalytic manifold will facilitate access to a range of heterobiaryl compounds and enable their applications across the fields of materials science, medicinal chemistry, and catalysis.Atropisomeric biaryls comprise a privileged class of compounds whose applications span the fields of medicinal chemistry, catalysis and materials science; as such, a panoply of elegant and efficient methods have been developedfor their synthesis 1 . The most convergent route to biaryls is generally the transition metal mediated cross-coupling of two partners 2,3 (although significant advances in metal-free methods have been demonstrated recently) 4 . Whilst this strategy generally results in cross-coupled products in good yields and predictable levels of chemo-and regioselectivity, these advantages may be offset by the requirement to synthesize two specifically functionalized coupling partners (Figure 1a) 5 . In principle, oxidative coupling represents a more direct, atom economic and environmentally benign approach as it creates the desired aryl-aryl linkage from two C-H bonds 6,7 . This realization has led to a significant number of oxidative homo-coupling procedures that can generate C2-symmetric BINOL-like structures in an enantioselective fashion. These include reactions mediated by transition metals including copper 8-10 , iron 11 and vanadium, 12 amongst others. However, in the absence of specific functional groups, controlling the regio-, chemo-and enantioselectivity of the corresponding hetero-couplings remains a formidable challenge, and successful examples have been limited to the synthesis of BINOL or NOBIN type scaffolds [13][14][15][16] . In particular, Katsuki demonstrated that iron salan complexes are effective in the enantioselective heterocoupling of naphthols 17 , and Pappo showed that chiral iron phosphate complexes act as effective precatalysts for the enantioselective synthesis of non C2-symmetric BINOLs (Figure 1b) 18 . We considered whether this oxidative cross-coupling approach could be used in the development of a method for the enantioselective synthesis of axially chiral indoles, which are emerging as a valuable member of the atropisomeric biaryl family 19-21 .

Ortho-selective C–H arylation of phenols with N-carboxyindoles under Brønsted acid- or Cu(i)-catalysis

“…Synthesis of axially chiral indolyl biaryl compounds has been previously realized by chiral Brønsted acid, 25 and transition metal catalysts. 26 However, given the unprecedented reversed polarity of indoles, it is highly intriguing whether the current heterobiarylation protocol can be rendered enantioselective. Toward this end, 1z having 4-Me and N -mesitylene carboxylate as a leaving group was prepared ( Scheme 3 ).…”