Atropisomeric compounds, owing to rotation restriction around an NÀC bond, have received much attention recently as novel chiral molecules.[1] ortho-tert-Butylanilide derivatives are typical examples of such atropisomeric compounds.[2] In 2005, we succeeded in the highly enantioselective synthesis of atropisomeric ortho-tert-butylanilides A and N-(ortho-tert-butylphenyl)lactams B through chiral, Pd-catalyzed, inter-and intramolecular N-arylation of achiral NHanilides.[3] These reactions were the first practical, catalytic, asymmetric synthesis of compounds with NÀC axial chirality. [4] After the publication of that work, [3a] catalytic, asymmetric syntheses of similar compounds with N À C axial chirality were reported by several other groups, all of which are of amide-type compounds, such as anilides, imides, and ureas. [5] On the other hand, the catalytic, asymmetric synthesis of non-amide compounds with NÀC axial chirality has not been reported so far.Several N À C axially chiral compounds with non-amide skeletons have also been found. [1a, 6] For example, Uemura and Kamikawa recently reported that indole derivatives possessing a 2,6-disubstituted phenyl group on the nitrogen atom (C) have a high rotational energy barrier around the N À Ar bond; however, in their synthesis of the optically active form, a stoichiometric chiral source is required.[6c] We predicted that similar to indoles C, N-(ortho-tert-butylphenyl)-indoles 1, also have stable atropisomeric structures.In this paper, we report the catalytic, enantioselective synthesis of axially chiral indoles 1 (non-amide compounds with NÀC axial chirality) through the chiral, Pd II -catalyzed, 5-endo-hydroaminocyclization of ortho-alkynylanilines. Furthermore, the stereochemical assignment of the axial chirality in indole products 1 is described.For a catalytic, asymmetric synthetic method for atropisomeric N-(ortho-tert-butylphenyl)indole derivative 1, we chose 5-endo-hydroaminocyclization of ortho-alkynylanilines. This reaction, which proceeds in the presence of a transition-metal catalyst or basic reagent, has been investigated by many groups as an efficient synthetic method of creating an indole skeleton, [7] but, to the best of our knowledge, its application to an asymmetric reaction has not been reported to date. We expected that optically active atropisomeric indoles 1 could be obtained through chiral, transition-metal-catalyzed (ML*) 5-endo-hydroaminocycliztion of achiral N-(ortho-tert-butylphenyl)-2-alkynylanilines 2 (Scheme 1).[a] N.

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By using Pd chemistry, a highly selective stereodivergent synthesis of separable amide rotamers was achieved. Allylation of 2,4,6-tri-tert-butylanilides using a pi-allyl-Pd catalyst gave N-allylated anilides with moderate-to-excellent Z-rotamer selectivity (Z/E = 3 to > 50). The Z-rotamer selectivity depends considerably on the substituent on the anilide substrates. On the other hand, the E rotamers of N-allylated 2,4,6-tri-tert-butylanilides were obtained with almost complete selectivity (E/Z > 50) through O-allylation of 2,4,6-tri-tert-butylanilides and the subsequent Pd(II)-catalyzed Claisen rearrangement of the resulting O-allyl imidate. The prepared anilide rotamers changed to equilibrium mixtures in which the E rotamer was the major isomer when heated in toluene.

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Herein, we report a unique structural property of 2,4,6-tri-tert-butylanilide, which can be separated into its amide rotamers at room temperature. Interconversion between the rotamers of anilide enolates occurs readily at room temperature and their reaction with electrophiles gives mixtures of the rotamers in a ratio that depends on the reactivity of the corresponding electrophile. That is, the reaction of the 2,4,6-tri-tert-butylacetanilide enolate with reactive electrophiles, such as allyl bromide or protic acids, gives mixtures of the anilide rotamers in which the E rotamer is the major component, whereas less-reactive electrophiles, such as 1-bromopropane and 2-iodopropane, yield mixtures of the rotamers in which the Z rotamer is the major component. The rotameric ratio of the product is also strongly dependent on the reactivity of the anilide enolate. Switching between the anilide rotamers can be achieved through protonation of a less-reactive enolate by a less-reactive protic acid and thermal isomerization of the anilide.