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meta C-H Arylation of Electron-Rich Arenes: Reversing the Conventional Site-Selectivity Luo-Yan Liu, Jennifer X Qiao, Kap-Sun Yeung, William R. Ewing, and Jin-Quan Yu J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b07887 • Publication Date (Web): 26 Aug 2019 Downloaded from pubs.acs.org on August 26, 2019
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meta C−H Arylation of Electron-Rich Arenes: Reversing the Conventional Site-Selectivity Luo-Yan Liu,† Jennifer X. Qiao,‡ Kap-Sun Yeung §, William R. Ewing, ‡ and JinQuan Yu*,† †Department
of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, California 92037, United States
‡
Discovery Chemistry, Bristol-Myers Squibb, PO Box 4000, Princeton, New Jersey 08543, United States
§
Discovery Chemistry, Bristol-Myers Squibb Research and Development, 100 Binney Street, Cambridge, MA 02142.
*
[email protected] RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required according to the journal that you are submitting your paper to)
Abstract. Controlling site-selectivity of C–H activation without using a directing group remains a significant challenge. While Pd(Ⅱ) catalysts modulated by a mutually repulsive pyridine type ligands have been shown to favor the relatively electron-rich carbon centers of arenes, reversing the selectivity to favor palladation at the relatively electron deficient positions has not been possible. Herein we report the first catalytic system that effectively performs meta C–H arylation
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of a variety of alkoxy aromatics including 2,3-dihydrobenzofuran and chromane with exclusive meta site-selectivity, thus reversing the conventional site selectivity governed by native electronic effects. The identification of an effective ligand and modified norbornene (NBE-CO2Me), as well as taking advantage of the statistics are essential for achieving the exclusive meta-selectivity.
1. Introduction C–H activation reactions without using a directing group offer synthetic utility that are complementary to the extensively developed chelation-assisted C–H activation reactions. In this context, development of Pd(Ⅱ)-catalyzed non-directed C–H activation reactions have been hampered by the following two limitations: lack of reactivity when 1.0 equiv. of an arene is used;1 achieving site-selectivity based on electronic and steric effects have met with tremendous difficulties.2 Although ligand enabled reactivity with arenes as limiting reagents has been reported recently,2 approaches to control the site selectivity of these reactions are lacking. The lack of site selectivity of Pd(Ⅱ)-catalyzed non-directed C–H activation is partially due to the ineffective recognition of steric effects by Pd(Ⅱ) catalysts. For example, non-directed C–H activation reactions of electron-rich arenes with Pd(Ⅱ) catalysts predominantly afford a mixture of ortho and para-products.2 We therefore proposed to introduce a bulky transient reaction partner to improve the selectivity based on steric effects. Based on our previous research on modified norbornene-assisted directed meta C–H functionalization,3,4,5 we envisioned that C–H palladation of electron-rich arenes followed by norbornene insertion could favor the sterically less-hindered para-positions. In addition, norbornene insertion at either ortho or para-positions could relay the final C–H arylation to the same meta-positions, thereby statistically enhancing the site selectivity.
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Most interestingly, this approach will reverse the conventional site-selectivity of electron-rich arenes to afford the meta-selective C–H arylation. Alkoxy aromatics are ubiquitous in natural products and drug molecules, as well as versatile coupling partners through recent nickel chemistry (Scheme 1).6,7 Since alkoxy groups are ortho and para directors for electrophilic palladation reactions, reversing this site-selectivity to instead favor meta C–H functionalization of alkoxyarenes would enable new strategies for arene synthesis. We have previously reported meta selective C–H functionalization of phenol using a tailor designed U-shaped template (Scheme 2a).8,9 Larrosa group developed a two-step sequence in one pot, namely, installation of a carboxylic group to direct ortho-C–H arylation and subsequent removal of the carboxylic group, to realize a formal meta-C–H arylation of phenol (Scheme 2b).10 However, these two approaches are not compatible with phenyl ethers such as dihydrobenzofurans or chromanes which do not contain the free hydroxyl group. Herein we report the first catalytic system that performs non-directed meta selective C–H arylation of a variety of electron-rich alkoxy aromatics (Scheme 2c), thus reversing the conventional site selectivity governed by native electronic effects. The use of a modified norbornene (NBE-CO2Me) to relay the initial ortho and para-palladation to meta-palladation is crucial for the observed site selectivity. Scheme 1. Bioactive Compounds Containing Phenols OH
OH
Me
O H
H
Me
Me
Ketobemidone
H
Me H N O
OH N O
Me N Me
Tramadol
Me H Me Me N Me H
Me HO
O
NH Et
NH
O
H Nelfinavir
H
HO
Picenadol
H
S
OMe
N Me
N Me
OH
H
Me
Toliprodol
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H Tasimelteon
O
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Scheme 2. Methods for meta C–H Activation of Phenols (a) meta-C–H Activation Directed by U-shaped Templates OMe
NC O O
N
O N
N NC
Me
H
O
H
N H
Me Template Strategy (Yu, 2013)
Norbornene Strategy (Yu, 2016)
N N
Template Strategy (Yu, 2019)
(b) meta-C–H Activation Directed by Traceless Directing Groups OH
OH
OH
CO2
CO2
CO2H
CO2H
OH
Ar
Ar
(c) Non-Directed Approach OR ortho
via
RO
Pd
OR H
[Pd] H
OR
H
FG
via
Native reactive sites for electrophilic palladation
OR
Pd(II)
H
H
H Pd
H
OR
para Pd(II)
2. Results and Discussion To implement the relay strategy using NBE-CO2Me, we selected anisole as the model substrate for reaction optimization and began our study by treating the model substrate (anisole, 1.0 equiv.) with aryl iodide (methyl 4-iodobenzoate, 2.0 equiv.), Pd(OAc)2 (15 mol%), modified norbornene (NBE-CO2Me) (1.5 equiv.), and AgOAc (3.0 equiv.) in HFIP (solvent) at 95 oC (Table 1). Encouragingly, the desired meta-arylation products were detected in 15% mono and di combined yield (entry 1). Guided by our recent finding that electron-deficient 2-pyridone ligands can accelerate non-directed C–H activation,2a,2d we wondered whether pyridone would also help this
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norbornene mediated arylation. Disappointedly, the optimal 2-pyridone ligand (L1) only improved the total yield to 25%. MPAA (mono-protected amino acid) ligand only afforded slightly increased yield. A variety of pyridine and quinoline ligands were also examined. While electron-rich pyridine-based ligands shut down the reaction (L2-3), a significantly enhanced yield was obtained when electron-deficient pyridine-based ligands were used (L5-7). Notably, quinoxaline improved the total yield to 58% (L6). Extensive screening of pyridine and quinoxaline-based ligands revealed that 6-cyanoquinoxaline was the best ligand for this non-directed arylation reaction, affording the combined mono and di meta-arylation products in 69% yield (L7). As a control experiment, L7 alone in the absence of NBE-CO2Me failed to provide any reactivity, thus highlighting the importance of NBE-CO2Me in this meta-selective arylation reaction (entry 12). The desired products were obtained in 63% yield when using 0.5 equiv. of NBE-CO2Me instead of 1.5 equiv. (entry 13). Table 1. Evaluation of Ligands a,b I
OMe + H
H
CO2Me
Entry
Ligand (NBE, Y/N)
1 2
Pd(OAc)2 (15 mol%) NBE-CO2Me (1.5 equiv.) L (30 mol%) AgOAc (3.0 equiv.) HFIP (0.4 M) 95 oC, 20 h
OMe
Ar
H/Ar
Ar = p-CO2MeC6H4
Yield (%) mono
di
total
No Ligands (Y)
11
4
15
Ac-Gly-OH (Y)
13
6
19
3
L1 (Y)
17
8
25
4
L2 (Y)
-
-
