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Enantioselective Arylative Dearomatization of Indoles via Pd-catalyzed Intramolecular Reductive Heck Reactions Chong Shen, Ren-Rong Liu, Ren-Jie Fan, Ying-Long Li, Teng-Fei Xu, Jian-Rong Gao, and Yi-Xia Jia J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b01705 • Publication Date (Web): 07 Apr 2015 Downloaded from http://pubs.acs.org on April 9, 2015
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Journal of the American Chemical Society
Enantioselective Arylative Dearomatization of Indoles via Pdcatalyzed Intramolecular Reductive Heck Reactions Chong Shen, Ren-Rong Liu, Ren-Jie Fan, Ying-Long Li, Teng-Fei Xu, Jian-Rong Gao, and Yi-Xia Jia* College of Chemical Engineering, Zhejiang University of Technology, Hangzhou 310014, China Supporting Information Placeholder ABSTRACT: A highly enantioselective intramolecular arylative dearomatization of indoles was developed via palladiumcatalyzed reductive Heck reactions. The new strategy led to a series of optically active indolines bearing C2-quaternary stereocenters in modest to good yields and excellent enantioselectivities (up to 99% ee).
Enantioselective dearomatization of arenes has emerged as an important transformation approaching a variety of optically active alicyclic systems, which constitute key moieties 1 of bioactive natural products and pharmaceuticals. Thanks to the effort devoted to this field, many elegant catalytic asymmetric dearomatization (CADA) reactions have been developed, such as the asymmetric hydrogenation of het2 eroarenes, oxidative dearomatizations and alkylative 1d,e dearomatizations. In contrast, asymmetric arylative dearomatization has met with less success and still remained a challenging task. Among the few known methods, palladium-catalyzed cross-coupling of two aryl moieties that pioneered by the groups of Buchwald, Bedford, and You has been demonstrated as a reliable approach toward this chal3,4 lenge. A few examples have appeared in their enantioselective versions. In 2009, Buchwald and co-workers developed an elegant Pd-catalyzed intramolecular enantioselective dearomatization reaction of anilines, delivering chiral 3,33a disubstituted-3aH-indoles in excellent enantioselectivities. Soon after, Buchwald and You independently reported arylative dearomatizations of phenols and indoles, while quite a 3d,e few examples were tested in the enantioselective fashion. Notably, very recently, success has been achieved for the asymmetric arylative dearomatization of phenols by Tang and co-workers, accessing chiral phenanthrenone derivatives 3h in high enantioselectivities. Obviously, all the aforementioned examples covering the racemic versions are only limited to aromatic substrates bearing free N-H or O-H bonds, such as aniline, indole, pyrrole, and phenol. Indeed, ketoenol tautomerism of such aromatic compounds under basic condition facilitates the dearomatization and subsequent carbon-carbon cross-coupling under Pd(0) catalyst. Undoubtedly, novel asymmetric dearomative arylation process based on the development of new strategies is highly attractive. In recent years, transition-metal-catalyzed direct arylation of CAr-H bonds of (hetero)arenes offers an efficient access to
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biaryl compounds, where Heck-type arylation has been pro6 posed as a possible mechanism. We envisaged that new arylative dearomatization reaction might be realized through an 7 intramolecular reductive Heck reaction, if suitable substituent was introduced onto the reactive site to prevent biaryl compound formation, and meanwhile the generated alkylpalladium intermediate was trapped by proper hydride sources. Following this hypothesis, we investigated the intramolecular asymmetric arylative dearomatization of Nsubstituted indoles via palladium-catalyzed reductive Heck 8,9 reactions (Figure 1). The new dearomatization strategy provides a facile approach to chiral indolines bearing C210 quaternary stereocenters, which are frequently occurring core structures of bioactive natural products, such as trigo11 12 13 noliimine C, (-)-isatisine A, and hinckdentine A. Herein, we wish to present our findings of highly enantioselective Pd-catalyzed arylative dearomatization of a variety of indole derivatives. Asymmtric arylative dearomatization of aniline (ref 3a) Br R R Pd(0)/L* N H
N
Asymmtric arylative dearomatization of phenol (ref 3d, 3h) Br
R
R
Pd(0)/L* OH
O
This work: Arylative dearomatization of N-protected indole XR Pd(0) L*
2
R
N
R1
O
R
PdX
R
2
[H]
R
N
2
N
R
R1
O H N
N
R1
O O
O
NH Br Br
O N H
N H
NHCOH Trigonoliimine C
N O OH OH (-)-Isatisine A
OH
N Br N Hinckdentine A
Figure 1. Methods for palladium-catalyzed asymmetric arylative dearomatizations and selected natural products containing C2-quaternary substituted indoline framework At the outset, the asymmetric reductive Heck reaction of N-(2-bromobenzoyl)-2-methylindole 1a was studied with HCO2H/NEt3 as a hydride source, Pd(OAc)2 as a catalyst, and
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(R)-BINAP as a ligand. As shown in Table 1, the reaction in o THF or Toluene at 100 C did not afford any arylative product (Table 1, entries 1-2). To our delight, the desired product 2a was isolated in lower yields but with excellent enantioselectivities when the reactions were performed in CH3CN or DCE (1,2-dichloroethane) (Table 1, entries 3-4). Gratifyingly, the yield was remarkably improved to 79% in methanol and the excellent enantioselectivity was retained (Table 1, entry 5). Comparable results were observed for reactions in EtOH and i PrOH (Table 1, entries 6-7). Other amines (TMEDA, DIPA, DABCO, and DBU) combined with HCO2H were then examined as hydride sources in MeOH, which gave similar results as that with NEt3 (Table 1, entries 8-11). However, the results were significantly improved when HCO2Na was used as a hydride source, leading to product 2a in 85% yield and 97% ee value (Table 1, entry 13). Subsequent ligand screening indicated that generally bidentate phosphines were efficient chiral ligands. The reactions with (R)-Tol-BINAP or (R)SYNPHOS as ligands also provided indoline 2a in good yields and excellent enantioselectivities, whereas relatively lower ee value was observed for (R)-SEGPHOS (Table 1, entries 14-16). o Finally, lowering the temperature to 80 C afforded 2a in comparable results albeit with a longer reaction time (Table 1, entry 17). Therefore, the best results were obtained under the conditions: 5 mol% Pd(OAc)2, 6 mol% (R)-BINAP, and 2.0 o 14 equiv. HCO2Na in 2.0 mL methanol at 100 C for 10 h.
Table 1. Optimization of the reaction conditionsa
Entry
L*
Base
Solvent
Yield(%)
1
L1
NEt3
THF
