A new method for the enantioselective synthesis of hexahydro-1H-benz[f]indoles is described. This copper-catalyzed enantioselective intramolecular alkene carboamination process can install vicinal tertiary and quaternary carbon stereocenters with high levels of diastereo-and enantioselectivity. The C-C bond-forming component of the reaction constitutes a C-H functionalization and no electronic activation of the aryl ring that undergoes addition is required. A known 5-HT 1A receptor antagonist was synthesized efficiently using this method.The intramolecular carboamination of alkenes is an attractive method for the synthesis of nitrogen heterocycles.1 This reaction has benefited particularly from methods involving palladium, copper and gold catalysis.2 , 3 In recent years, the catalytic asymmetric carboamination has been actively pursued. One approach involves the doubly intramolecular enantioselective carboamination wherein intramolecular alkene amination is followed by addition of the resulting reactive carbon intermediate to a π-bond tethered through the Nsubstituent. In this manner, Pd(II)2c and Cu(II)3a complexes have catalyzed formation of chiral bicyclic lactams and sultams, respectively.We desired to apply the copper-catalyzed carboamination reaction to the synthesis of other nitrogen heterocycles and believed that the proposed carbon radical intermediate,3c e.g., A (Scheme 1) could add to other nearby π-bonds.This reaction could in principle be (1) chemoselective, choosing radical addition either to an N-arylsulfonyl ring (as previously reported)3a or an aromatic ring at the allylic position (as in Scheme 1), (2) diastereoselective, choosing between formation of either a cis or trans ring fusion, and (3) Our initial forays into the copper-promoted carboamination of N-mesyl substrate 1a were promising. Using 300 mol % of Cu(OAc) 2 , the cis-fused hexahydrobenz[f]indole 2a was obtained in 64% yield with >20:1 diastereoselectivity (Scheme 1).6 Encouraged by this result, we submitted 1a to catalytic, enantioselective conditions.3a To our delight, we obtained a 99% yield and 82% ee, with >20:1 diastereoselectivity using 20 mol % Cu(OTf) 2 , 25 mol % (R, R)-Ph-box, 300 mol % MnO 2 at 120 °C in PhCF 3 for 24 h (Figure 1, 2a).The trimethylsilylethylsulfonyl substrate 1b (R = SES) underwent the reaction with equal efficiency (Figure 1, 2b). Various arylsulfonyl substrates 1c-1g (R = Bs, Ts, PMBS, PCBS, Ns) provided hexahydro-1H-benz[f]indole adducts 2c-2g with even higher enantioselectivity (94-97% ee) and no trace of the sultam3a regioisomer. Substrates 1h-j with para aryl ring substitution (X = F, SMe, OMe) provided uniformly high yields and enantioselectivities.The meta-MeO substrate 3a gave the benz[f]indoles 4 as a 1.5:1 mixture of ortho and para regioisomers (with respect to aryl addition).3cInterestingly, substrates with ortho substitution, 5a and 5b, gave regioisomers 6 and 7 where 7 is the result of a rearrangement where an aryl substituent has apparently shifted to the meta-position. This can be...
