Chiral Brønsted acid-catalyzed Friedel–Crafts alkylation of electron-rich arenes with in situ - generated ortho -quinone methides: highly enantioselective synthesis of diarylindolylmethanes and triarylmethanes †

We disclose herein a highly enantioselective protocol for the Brønsted acid-catalyzed addition of indoles and phenols to in situ - generated ortho -quinone methides which deliver broadly substituted diarylindolylmethanes and triarylmethanes, respectively, in a one-pot reaction under very mild conditions. A chiral phosphoric acid catalyst has been developed for this process serving to convert the starting ortho -hydroxybenzhydryl alcohols into the reactive ortho -quinone methides and to control the enantioselectivity of the carbon–carbon bond-forming event via hydrogen-bonding.

Triarylmethanes have gained substantial attention from the synthetic community because of their importance in medicinal chemistry, materials science and as dye precursors. 1 Several of them are known to be potential drug candidates for the treatment of cancer, bacterial infections, and diabetes 2 and are also core structures in natural products such as for example in cassigarol B. 3 Similarly, heteroaryl-substituted analogues of this product class have been shown to be powerful pharmaceuticals and bioactive molecules like letrozole, vorozole, and paraphenyl-substituted diindolylmethanes. 4Accordingly, novel synthetic methods to access enantiomerically highly enriched triarylmethanes and related compounds continue to be highly desirable.
Although a variety of racemic routes have been developed 5 only a few enantioselective syntheses are currently available based upon reports from the groups of Jarvo, 6 Watson, 7 and Crudden 8 who employed asymmetric cross-coupling technology to construct the target triarylmethanes in the optically highly enriched form.Apart from that You, 9 Zhang, 10 and Han 11 developed Brønsted acid-catalyzed, enantioselective syntheses of special aryldiindolylmethanes starting from both aryl(3-indolyl)methanols and aryl(2-indolyl)methanols.
Recently, we have disclosed the phosphoric acid-catalyzed, highly enantioselective conjugate addition of 1,3-dicarbonyl compounds to in situ generated ortho-quinone methides (o-QM). 12his strategy was applied to a one-pot and straightforward synthesis of optically highly enriched 4-aryl-4H-chromenes and related heterocycles through a subsequent cyclodehydration reaction (Scheme 1, pathway a).o-QM constitute highly reactive synthetic intermediates participating easily in conjugate additions, hetero Diels-Alder reactions, and 6p-electrocyclizations. 13 It was only recently that a range of catalytic, enantioselective processes have been successfully developed for o-QM chemistry including palladium-, cinchona alkaloid-, BINOL-and NHC-catalyzed reactions. 14n continuation of our interest in enantioselective reactions of hydrogen-bonded o-QM we now report that both indoles and naphthols are highly suitable nucleophiles for this purpose and deliver broadly substituted diarylindolylmethanes and triarylmethanes with excellent yields and enantioselectivities (Scheme 1, pathway b).Bach and coworkers pursued this strategy previously and obtained some addition products with moderate enantioselectivity. 15Very recently Sun et al. have shown that tertiary benzylic alcohols can form triarylmethanes that carry exclusively quaternary chiral centers upon indole addition. 16his journal is © The Royal Society of Chemistry 2015 We initiated our studies by investigating the reaction of ortho-hydroxybenzhydryl alcohol 1a (1 equiv.)with indole (2a) (1.2 equiv.) in CH 2 Cl 2 in the presence of various chiral phosphoric acids 3a-g (5 mol%) (Table 1).The (F-C) adduct 4a was obtained in good yields in almost all cases within 2.5 h at room temperature.Systematic screening of the catalysts further revealed that sterically demanding 3,3 0 -aryl substituents in the BINOLbackbone of the Brønsted acid catalyst gave improved enantioselectivities.An optimal selectivity was eventually obtained with phosphoric acid 3d (Ar = 2,6-Me 2 -4-t BuC 6 H 2 ) which delivered the (F-C) addition product 4a with 94% yield and 91 : 9 er (Table 1, entry 4).Solvents like toluene and CH 3 CN were found to be inferior as compared to CH 2 Cl 2 , reducing the selectivity to 79 : 21 er and 81 : 19 er, respectively, albeit in excellent yields (entries 9 and 10).The amount of indole was further reduced to 1.0 equiv.without compromising the yield or selectivity of the reaction.Under these conditions the (F-C) adduct was isolated in 92% overall yield and with 92 : 8 er (entry 11).It is important to note that the free NH-moiety within the indole component is crucial for high enantioselectivity presumably via additional hydrogen-bonding to the phosphoric acid catalyst. 17o evaluate the scope of this process various ortho-hydroxy benzhydrols 1b-m were subsequently reacted with indole (2a) under the above-optimized reaction conditions and the results are summarized in Table 2.In almost all cases studied, the reaction proceeded smoothly and was typically completed within 2-12 h at rt.The products 4b-m were obtained in excellent yields and with good to excellent enantioselectivities (entries 1-12).A range of substituents was readily accommodated at various positions both within the o-QM fragment as well as the b-aryl substituent delivering the products with excellent results as well.
A crystal structure of diarylindolylmethane 4c (entry 2) obtained by slow evaporation of CH 2 Cl 2 revealed its absolute configuration which was assigned to all other products as well (Fig. 1). 18n addition, the influence of various functional groups and substituents in the indole component was investigated in this study (Table 3).These results clearly reveal an excellent functional group tolerance of this process and a broad set of heteroaryl-substituted triarylmethanes was obtained in good yields and enantioselectivities irrespective of the electronic properties of the substituents on the indole ring.
Challenging substituents like phenol, formyl, acid, cyano, ester, ether, and halide groups did not interfere with this process and   furnished the desired (F-C) addition products in good to excellent enantioselectivities and high yields.The ability to withstand all these functional groups without compromising the yield or selectivity is testimony to the scope of this methodology.The excellent results obtained for indoles inspired us to pursue this strategy further and extend it to electron-rich naphthols which are also known to be excellent substrates to undergo (F-C) alkylation reactions.A range of Brønsted acid catalysts were screened for the (F-C) alkylation of 2-naphthol (15a) with ortho-hydroxybenzhydrol 1a (see the ESI †).It turned out that in the presence of 5 mol% of catalysts 3a, 3c, and 3d, respectively, the unsymmetrically substituted triarylmethanes were obtained in excellent yields in all cases studied.The highest enantioselectivity was obtained again with catalyst 3d when 4 Å MS was used as an additive in CH 2 Cl 2 as the solvent at room temperature.
With these conditions established we examined a range of 2-naphthols in reactions of hydrogen-bonded o-QM (Table 4).A series of differently substituted ortho-hydroxybenzhydryl alcohols were tested as o-QM precursors (entries 1-7).In almost all cases studied the triarylmethanes 17a-g were isolated in excellent yields and with 496 : 4 er.Further substitution within the 2-naphthol ring with halogen, ester, ether, and aryl substituents was readily tolerated and delivered the products 17h-m in comparably high yields and enantioselectivities (entries 8-13).Quite interestingly, 1-naphthol ( 16) worked equally well as the substrate and furnished triarylmethane 18 in almost quantitative yield and 93 : 7 er (entry 14).
To further reveal the synthetic potential of this new process some of the diarylindolylmethanes were subsequently converted into highly versatile dihydrochromeno[2,3-b]indoles 19a-b through a one-pot bromination followed by cyclization and base-catalyzed elimination (Scheme 2).14h The products were obtained in good yields and retained their optical purity almost completely.
On the basis of the crystal structure which we obtained for the (F-C)-product 4c, we propose a transition structure as shown in Fig. 2, which accommodates double hydrogen-bonding of the catalyst to both the o-QM and the nucleophile and intramolecular delivery of the nucleophile to the re-face of the o-QM because the opposite face is effectively shielded by the neighbouring 3 0 -Ar-group. 19n summary, we have developed a highly efficient, Brønsted acid-catalyzed (F-C)-alkylation of electron-rich indoles and  a All reactions were carried out with 0.2 mmol (1 equiv.) of 1, 0.24 mmol (1.2 equiv.) of naphthols 15a-g and 16 using 5 mol% of catalyst 3d in 2 mL of CH 2 Cl 2 at rt for 4-6 h in the presence of a catalytic amount of

Table 1
Optimization studies a a All reactions were carried out with 0.23 mmol (1 equiv.) of 1a, 0.27 mmol (1.2 equiv.) of 2a and 5 mol% of catalyst 3a-3f in 3 mL of CH 2 Cl 2 at rt. b Isolated yield of the purified product.c Er determined through chiral HPLC-analysis (see the ESI).d Reaction was carried out at 0 1C.e 1.0 equiv. of indole (2a) was used as the substrate.

Table 2
Substrate scope a a All reactions were carried out with 0.42 mmol (1 equiv.) of 1b-m, 0.42 mmol (1.0 equiv.) of indole (2a) and 5 mol% of catalyst 3d in 4 mL of CH 2 Cl 2 at rt for 2-12 h.b Isolated yield of the purified product.c Er determined through chiral HPLC-analysis (see the ESI).

Table 3
Brønsted acid-catalyzed addition of substituted indoles 2b-j to ortho-hydroxybenzhydryl alcohols 1 a a All reactions were carried out with 0.42 mmol (1 equiv.) of 1, 0.42 mmol (1.0 equiv.) of indoles 2b-j and 5 mol% of catalyst 3d in 4 mL of CH 2 Cl 2 at rt for 2-12 h.b Isolated yield of the purified product.c Er determined through chiral HPLC-analysis (see the ESI).