Meta C-H Arylation of Electron-Rich Arenes: Reversing the Conventional Site Selectivity

Article abstract of DOI:10.1021/jacs.9b07887

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 ligand 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 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.

Full text of DOI:10.1021/jacs.9b07887

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Article
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
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Luo-Yan Liu,† Jennifer X. Qiao,‡ Kap-Sun Yeung §, William R. Ewing, ‡ and Jin-
Quan 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.
*yu200@scripps.edu
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.
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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.
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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 withphenyl 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.
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Scheme 1. Bioactive Compounds Containing Phenols
OH
OH
H
OMe
N
Me
Me
O
H
H
H
Me
HO
Me
N
Me
N
Me
Me
Ketobemidone
Picenadol
Tramadol
Me
OH
H
N
O
O
Me
Me
HO
NH
OH
H
N
H
Et
NH
H
Me
Me
Me
O
O
S
N
H
O
H
Me
H
Nelfinavir
Toliprodol
Tasimelteon
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Scheme 2. Methods for meta C–H Activation of Phenols
(a) meta-C–H Activation Directed by U-shaped Templates
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OMe
N
NC
O
N
O
O
N
H
N
O
N
NC
Me
N
H
H
Me
Template Strategy (Yu, 2013)
Norbornene Strategy (Yu, 2016)
Template Strategy (Yu, 2019)
(b) meta-C–H Activation Directed by Traceless Directing Groups
OH
OH
OH
CO2
OH
CO2
CO2H
Ar
CO2H
Ar
(c) Non-Directed Approach
OR
via
RO
Pd
H
ortho
para
OR
OR
Pd(II)
H
[Pd]
OR
Pd
H
H
FG
H
via
OR
Native reactive sites
for electrophilic
palladation
H
H
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
o
(NBE-CO2Me) (1.5 equiv.), and AgOAc (3.0 equiv.) in HFIP (solvent) at 95 C (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).
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Table 1. Evaluation of Ligands a,b
Pd(OAc)2 (15 mol%)
NBE-CO2Me (1.5 equiv.)
I
OMe
OMe
L
(30 mol%)
+
AgOAc (3.0 equiv.)
HFIP (0.4 M)
H
H
Ar
H/Ar
CO2Me
95 oC, 20 h
Ar = p-CO2MeC6H4
Yield (%)
Entry
Ligand (NBE, Y/N)
mono
total
di
1
2
No Ligands (Y)
Ac-Gly-OH (Y)
11
13
17
-
4
15
19
6
8
L
1 (Y)
L
2 (Y)
L
3 (Y)
L
4 (Y)
L
5 (Y)
L
6 (Y)
L
7 (Y)
L
8 (Y)
3
25
4
-
<10
<10
24
5
-
-
6
16
35
40
46
23
50
-
8
7
15
18
23
10
26
-
50
8
58
9
69
10
11
12
13
33
L7 + L
8 (Y)
76
L
7 (N)
trace
63
L7 + L
8 (0.5 equiv.)
43
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Me
F3C
NHAc
OH
t-Bu
N
OMe
N
Cl
N
N
O
Me
L1
L2
L3
L4
6
7
8
9
CF3
N
N
NC
N
N
F3C
SO3H
N
N
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L5
L6
L7
L8
a Conditions: 1a (0.2 mmol, 1.0 equiv), aryl iodide (2.0 equiv.), Pd(OAc)2 (15 mol%), NBE-CO2Me (1.5
o
equiv.), L (30 mol%), AgOAc (3.0 equiv), HFIP (0.5 mL), 95 C, under air, 20 h. See SI for work up
procedures. b 1H NMR yields.
Considering the multiple steps involved in this complex catalytic cycle and the optimal ligand
for each step may differ, we have also tested a dual ligand system.2b,2c,2e Interestingly, the addition
of an electron-deficient 3-pyridinesulfonic acid as the second ligand (L8) improved the combined
yield to 76% (entry 11, see SI for detailed ligand screening). Control experiments show that L8
alone gave much lower reactivity than L7 (for control experiments with several other substrates,
see SI). 3-pyridinesulfonic acid L8 was previously used to promote sp3 C–H olefination.11 The
beneficial role of L8 is likely due to the formation of a more reactive cationic L7(L8)Pd+-OAc
complex which could bind the arene substrate more effectively (Scheme 3). The rationale for the
design of this type of anion-containing L-type ligand has been previously demonstrated.11
Scheme 3. Beneficial Effect of Dual Ligand System (L7, L8)
N
N
N
N
Ar-H, - OAc
H
N
N
Pd OAc
OAc
N
N
Pd
OAc
SO3
SO3
N
N
Ar-H
H
N
N
Pd
N
N
Pd
OAc
OAc
more reactive
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With the best conditions established, we next investigated the aryl iodide scope of this reaction
(Table 2). Using 3-methylanisole as the model substrate, the corresponding arylation products
were obtained in moderate to good yields and high regioselectivity with a series of aryl iodides
regardless of their electronic properties (2ba-2bj). Various 2-substituted pyridine-based
heteroaryl iodides are also compatible with this reaction (2bk-2bm). Several aryl iodides derived
from estrone, borneol and menthol were also effectively utilized to afford the desired products in
69%, 73% and 71% yields, respectively (2bn-2bp).
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Table 2. Scope of (Hetero)Aryl Iodides a,b
Pd(OAc)2 (15 mol%)
NBE-CO2Me (1.5 equiv.)
OMe
OMe
L
L
7 (30 mol%), 8 (15 mol%)
+
Ar-I
AgOAc (3.0 equiv.)
HFIP (0.4 M)
H
Me
Ar
Me
95 oC, 20 h
1b
2ba-2bp
N
CN
F3C
SO3H
L7
L8
=
=
N
N
OMe
OMe
OMe
OMe
OMe
OMe
Me
Me
Me
Me
Me
Me
MeO2C
F3C
O2N
F
Me
Ac
2ba
2bb
56%
2bc
2bd
2be
2bf
60% (74%c)
70%
62%
62%
62%
OMe
OMe
OMe
OMe
OMe
OMe
Me
MeO2C
Cl
Me
Me
Me
Me
Me
Me
N
TsO
Cl
N
Cl
2bk
2bl
2bg
2bh
2bi
2bj
74%c
52%c
54%
61%
48%
42%
OMe
OMe
OMe
OMe
Me
Me
Me
Me
Me
Me
Me
O
Me
Me
O
H
H
H
N
O
O
O
CF3
O
Me
Me
O
2bm
2bn
2bo
69%
2bp
77%c
71%
73%
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a Conditions: 1b (0.2 mmol), aryl iodides (2.0 equiv.), Pd(OAc)2 (15 mol%), NBE-CO2Me (1.5 equiv.), L7 (30
6
7
8
o
mol%), L8 (15 mol%), AgOAc (3.0 equiv), HFIP (0.5 mL), 95 C, under air, 20 h. See SI for work up
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procedures. b Isolated yields. c Aryl iodides were used as limiting reagents (1.0 equiv.), 2.0 equiv. of arenes.
A wide range of arenes were also examined in this meta-selective arylation reaction (Table 3).
Various functionalities on the 3-positions of anisole including ester, ether, silyl, alkyl, amide, and
phenyl groups were all well tolerated, affording the desired products in 56-78% isolated yields
(2c-2l). The reaction remained highly meta-selective when 2-isopropylanisole (2m) and 5-
methoxy-1,2,3,4-tetrahydro-naphthalene (2n) were used as the substrates. Notably, other readily
removable protecting groups of phenols such as isobutyl and TBS groups stayed intact during this
arylation reaction (2o-p). Surprisingly, 2-methylanisole (2q) only afforded the desired meta
product in 28% yield, which is much lower than 2-isopropylanisole (2m). Large substituents (2m)
at C-2 position would impede the norbornene-related second C–H activation at C-3, thus
selectively affording C-5 arylation product in good yield. However, the second C–H activation at
C-3 could still occur when C-2 substituent is small (2q), and yet this intermediate is not reactive
towards aryl iodide. Instead, reductive elimination led to the formation of the cyclobutane side
product (see SI for more information). para-Substituted anisole only gave trace amount of meta-
arylation product due to the steric hinderance of the methyl group (2r). No desired product was
observed with substrate containing strong electron-withdrawing groups (see SI for other
unsuccessful substrates).
2,3-Dihydrobenzofurans and chromanes, another class of electron-rich arenes, are ubiquitous in
drug molecules and natural products.12 Although meta-C–H functionalization of 1-indoline and
1,2,3,4-tetrahydroquinolines has been accomplished by attaching a tethered directing template to
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the nitrogen atom,13 this strategy is incompatible with 2,3-dihydrobenzofurans and chromanes.
Gratifyingly, our norbornene mediated non-directed strategy provided a solution to this long-
standing problem. Simple 2,3-dihydrobenzofuran was successfully arylated with high site-
selectivity in 48% isolated yield (2s). Substituents such as alkyl and ester groups on the C-2
position afforded good yields (2t, 2u). Esters and amides containing chromanes were also effective
substrates with high site-selectivity in 62-76% yields (2v-2y). More structurally complex
Table 3. Scope of Substrates a,b
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Pd(OAc)2 (15 mol%)
NBE-CO2Me (1.5 equiv.)
I
OR'
OR'
L
L
7 (30 mol%), 8 (15 mol%)
5
6
7
+
R
R
AgOAc (3.0 equiv.)
HFIP (0.4 M)
H
Ar
CO2Me
95 oC, 20 h
Ar-I
1c-1zg
2c-2zg
8
9
N
N
CN
F3C
SO3H
L7
L8
=
=
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N
OMe
OMe
OMe
OMe
OMe
OMe
Me
Me
OBn
CO2Me
OMe
Ar
Ar
Ar
NHAc
Ar
CO2Me
Ar
Ar
2c
2d
2e
2g
2h
2f
56%
60%
73%
68%
58%
OMe
58%
OMe
OMe
OMe
OMe Me
Me
OMe
Ar
Ar
Ar
Ar
SiMe3
Ar
Ar
CF3
Cl
2i
2j
2k
2l
2m
2n
70%
78%
65%
61%
51%
44%
OMe
OTBS
OiBu
OMe
OMe
Me
EWG = CO2R, NO2,
CHO, CF3, etc.
EWG
ArF
Me
Ar
Me
Ar
Me
2o
2p
2q
28%e
2r
< 5%
n.r.
52%d
51%
CO2Me
Me
CO2Me
NHAc
O
O
O
Ar
O
CO2Me
Ar
Ar
Ar
Ar
O
Ar
O
2w
2v
2t
2u
2s
48%f
2x
70%
63%
58%
59%
64%
O
O
Me
Et
NH
O
O
MeO
HN
Ar
O
Me
N
N
O
Me
O
Ar
O
O
H
Ar
O
Ar
Ar
O
O
Ar
2z
2zb Tasimelteon
2za
2zc
2zd
31%f
2y
76%
56%
77%
72%
41%
OEt
OBn
OTIPS
2zg
2ze
2zf
42%
73%
73%
10%g mono +32% di
46% mono +27% di
47% mono +26% di
Ar
Ar/H
Ar
Ar/H
Ar
Ar/H
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a Conditions: 1c-1zd (0.2 mmol), aryl iodide (2.0 equiv.), Pd(OAc)2 (15 mol%), NBE-CO2Me (1.5 equiv.), L7
5
6
7
o
(30 mol%), L8 (15 mol%), AgOAc (3.0 equiv), HFIP (0.5 mL), 95 C, under air, 20 h. See SI for work up
8
9
b
c
d
procedures. Isolated yields. No byproducts of arenes were observed in most cases. 4-Fluoro-1-
iodobenzene (ArF) was used instead of methyl 4-iodobenzoate for better separation on TLC. e Conversion
is 46% (see SI for information about major byproduct). f Other regiosiomers were observed in less than 5%.
g 1H NMR yield, inseparable from aryl iodides and NBE-CO2Me on TLC.
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chromanes with succinimide and pyrrolidone functionalities were successfully arylated (2z, 2za).
To showcase the synthetic utility of this method, non-directed meta C–H arylation of FDA
approved drug Tasimelteon was carried out to provide the potentially useful arylated product in 72%
yield (2zb). Other oxygen-containing heterocycles such as 1,4-benzodioxane and 2-
methoxydibenzofuran were also compatible substrates (2zc, 2zd). We also tested several
unsubstituted phenols with different protecting groups, such as ethyl, benzyl and TIPS. Ethyl and
benzyl protected phenols afforded the desired products in a combined yield of 73% with exclusive
meta-selectivity (2ze and 2zf). Bulky TIPS protected phenol gave 32% di product but only 10%
mono product (2zg), which is probably due to the large steric hinderance of TIPS. Furthermore,
meta-arylation of chromane derivative (1w) was carried out on 5.0 mmol scale, affording the
desired product in 58% yield (Scheme 4).
Scheme 4. Scale-up Reaction
I
CO2Me
CO2Me
'standard conditions'
+
O
H
O
MeO2C
CO2Me
2w
58%, 946 mg
1w
5.0 mmol, 960 mg
10.0 mmol, 2.0 equiv.
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Based on our design, the observed meta-C–H arylation proceeds through the initial palladation
at the ortho-position, which are then intercepted by the norbornene insertion followed by
subsequent Catellani C–H arylation (Scheme 5a). To obtain evidence for this proposed mechanism,
we performed deuterium incorporation experiments with ethoxybenzene under the standard
conditions in the presence of HFIP-ol-D (see SI for more details). The presence of 70% deuterium
incorporation at exclusively the C-2 position in the mono-arylated product suggests that the mono
arylation product was derived from ortho C−H palladation and the catalytic cycle is terminated by
the C-2 protonation (deuterium incorporation step) of the arylpalladium intermediate E (Scheme
5a). Interestingly, 27% D-incorporation at ortho-position and 55% D-incorporation at para-
position are observed in the di-arylated product. The para-deuteration originates from initial C–H
para-palladation and subsequent consecutive di-arylation as expected from the Catellani reaction.
Conceivably, the mono-arylated product could also undergo further ortho-palladation and
proceeds to give the di-arylation product, which could lead to the incorporation of the ortho-
deuterium. This hypothesis is experimentally supported by the D-labeling in the mono-arylation
of 1b in the (Scheme 5b).
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Scheme 5. Deuteration Experiments and Proposed mechanism
(a) Proposed mechanism
OR
OR
OR
non-directed C-H arylation
at ortho or para C-H
H
H
H
H
H
Ar
Ar
Ar
H
Pd(II)Ln
di product
mono product
C-H Activation
Norbornene Extrusion
OR
OR
Pd(II)Ln
Pd(II)Ln
Ar
(E)
(A)
Reductive Elimination
Norbornene Insertion
ortho C-H activation
OR
Ar
OR
(IV)
I
Pd
Pd(II)Ln
(B)
Ln
(D)
Oxidative Addition
OR
C-H Activation
Pd(II)
Ln
(C)
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OR
OR
4
5
6
Ar
Ar
H
H
di product
7
Pd(II)Ln
Norbornene Extrusion
C-H Activation
8
9
OR
Ar
LnPd(II)
OR
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Ar
Pd(II)Ln
(K)
(F)
Oxidative Addition
then Reductive Elimination
Norbornene Insertion
Ln
para C-H activation
(II)Pd
OR
OR
Pd(II)
Ar
Ln
(J)
(G)
Reductive Elimination
then C-H Activation
C-H Activation
OR
OR
(IV)
Pd
Ln
I
Pd(II)
Ar
Ln
(I)
Oxidative Addition
(H)
(b) Deuteration experiments
OEt
OEt
H
I
OEt
H/D
Ar
H/D
H
H
H/D(70%D)
Ar
standard conditions
H
H
H
H
+
+
Ar
HFIP-ol-D
H/D(55%D)
CO2Me
H
24%
46%
0.2 mmol
2.0 equiv.
I
OMe
OMe
H
standard conditions
HFIP-ol-D
H/D(66%D)
Ar
H/D
Me
H
H
H
+
Me
CO2Me
H/D(24%D)
66%
0.2 mmol
2.0 equiv.
1b
3. Conclusion
In conclusion, we have developed the first example of non-directed meta C–H arylation of
electron-rich arenes. This reaction features broad substrate scope and good functional group
compatibility, exemplified by successful C–H arylation of a range of complex molecules and FDA
approved drug molecule Tasimelteon. Importantly, the ortho- and para-C–H palladation
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intermediates are not arylated prior to being intercepted by the NBE-CO2Me, thus affording
exclusive meta-arylation products and reverses the conventional site selectivity of electron-rich
arenes. Efforts to develop other transformations guided by similar design are currently underway
in our laboratory.
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4. Experimental Section
General procedure for non-directed meta C–H arylation: Alkoxybenzene (0.2 mmol), aryl
iodide (2.0 equiv.), Pd(OAc)2 (15 mol%), modified norbornene (1.5 equiv.), L7 (30 mol%), L8 (15
mol%), AgOAc (3.0 equiv.), and HFIP (0.5 ml) were added to a reaction vial (10 ml). The vial
was capped and closed tightly. Then the reaction mixture was stirred at 95 °C for 20 hours. After
cooling to room temperature, the mixture was passed through a pad of celite with ethyl acetate as
the eluent to remove the insoluble precipitate. The resulting solution was concentrated and purified
by preparative thin-layer chromatography to afford the desired product.
Corresponding author. *yu200@scripps.edu
Notes. The authors declare no competing financial interest.
Acknowledgements. We gratefully acknowledge The Scripps Research Institute and the NIH
(National Institute of General Medical Sciences grant R01 GM102265) for financial support. We
gratefully acknowledge Dr. Jason Chen (TSRI), Brittany Sanchez (TSRI) and Emily Sturgell
(TSRI) for HRMS analysis and compound purification.
Supporting Information Available: Experimental procedures and spectral data for all new
compounds (PDF). This material is available free of charge via the Internet at http://pubs.acs.org.
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TOC Graphic
5
OR
OR
6
CO2Me
7
8
9
H
H
Ar
O
Pd
Dual Ligands
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O
O
H
O
H
Ar
Ar
Exclusive meta-Selectivity
Overriding the Electronic Effect
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