Entry to 1,2,3,4-Tetrasubstituted Arenes through Addressing the " Meta Constraint" in the Palladium/Norbornene Catalysis

Article abstract of DOI:10.1021/jacs.9b12355

Arenes with four different contiguous substituents, i.e. 1,2,3,4-tetrasubstituted arenes, are commonly found in bioactive compounds, but they are nontrivial to access via conventional methods. Through addressing the "meta constraint" in the palladium/norbornene (Pd/NBE) cooperative catalysis, which is the difficulty of tolerating a sizable meta substituent in aryl halide substrates, here a modular and regioselective approach is realized for preparing 1,2,3,4-tetrasubstituted arenes. One key is the use of a C2-amide-substituted NBE, and a combined experimental and computational study reveals its role in promoting the NBE insertion and the ortho C-H metalation steps. The scope is broad: A variety of electrophiles and nucleophiles could be introduced to the ortho and ipso positions, respectively, with 1,4-disubstituted aryl halides, leading to diverse unsymmetrical contiguous tetrasubstituted arenes. Application of this approach has been demonstrated in streamlined syntheses of several bioactive compounds.

Full text of DOI:10.1021/jacs.9b12355

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Article
Entry to 1,2,3,4-Tetrasubstituted Arenes through Addressing
the “Meta Constraint” in the Palladium/Norbornene Catalysis
Jianchun Wang, Yun Zhou, Xiaolong Xu, Peng Liu, and Guangbin Dong
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b12355 • Publication Date (Web): 24 Jan 2020
Downloaded from pubs.acs.org on January 24, 2020
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Page 1 of 20
Journal of the American Chemical Society
Entry to 1,2,3,4-Tetrasubstituted Arenes through Addressing the “Meta
1
2
3
4
Constraint” in the Palladium/Norbornene Catalysis
5
6
Jianchun Wang†‡, Yun Zhou†‖‡, Xiaolong Xu†#, Peng Liu§, and Guangbin Dong*†
7
8
9
10
11
12
13
14
15
16
† Department of Chemistry, University of Chicago, Chicago, Illinois 60637, United States
‖ Department of Applied Chemistry, China Agricultural University, Beijing 100193, China
# School of Physical Science and Technology, ShanghaiTech University, Shanghai 201210, China
§ Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States
ABSTRACT: Arenes with four different contiguous substituents, i.e. 1,2,3,4-tetrasubstituted arenes, are
commonly found in bioactive compounds, but they are non-trivial to access via conventional methods. Through
addressing the “meta constraint” in the palladium/norbornene (Pd/NBE) cooperative catalysis, which is the
difficulty of tolerating a sizable meta substituent in aryl halide substrates, here a modular and regioselective
approach is realized for preparing 1,2,3,4-tetrasubstituted arenes. One key is the use of a C2-amide-substituted
NBE, and a combined experimental and computational study reveals its role in promoting the NBE insertion and
the ortho C−H metalation steps. The scope is broad: a variety of electrophiles and nucleophiles could be
introduced to the ortho and ipso positions, respectively, with 1,4-disubstituted aryl halides, leading to diverse
unsymmetrical contiguous tetrasubstituted arenes. Application of this approach has been demonstrated in
streamlined syntheses of several bioactive compounds.
17
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INTRODUCTION
Polysubstituted arenes commonly exist in natural products, pharmaceuticals and agrochemicals (Scheme
1A).1 While numerous effective arene functionalization approaches have been developed to date, it is non-trivial
to regioselectively construct unsymmetrical contiguous tetrasubstituted arenes, i.e. 1,2,3,4-tetrasubstituted
benzenes, with each substituent being different (Scheme 1B).2 For example, electrophilic aromatic substitution
(EAS) of a 1,2,3-trisubstituted arene could encounter a site-selectivity issue (C4 vs C6 positions). In addition,
directed C−H activation strategies3 could provide the desired site-selectivity yet the use of a directing group (DG)
is required. The aryne chemistry offers a unique opportunity for vicinal difunctionalization, but, to generate
benzynes from aromatic substrates, it typically requires either strong bases or pre-difunctionalized arenes.4 Apart
from arene functionalization methods, the 1,2,3,4-tetrasubstituted arenes could also be prepared via the
Diels−Alder reaction, though it has been challenging to control regioselectivity for unsymmetrical substrates.5
Hence, a modular and general approach to access aromatic compounds that contain four contiguous different
substituents remains highly sought after.
Scheme 1. Synthesis of 1,2,3,4-tetrasubstituted arenes
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A.
Examples of bioactive compounds containing 1,2,3,4-tetrasubstituted arenes
1
2
3
4
5
6
MeO
HO
OH
NHMe
NMe
Me
HO
S
Me
H
O
N
N
H
H
O
OH
H
O
7
totarol
S1319
domesticine
daphenylline
8
9
B.
Existing approaches for synthesizing 1,2,3,4-tetrasubstituted arene
10
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= DG
1
6
EAS
activation
C-H
4
?
e
[4+2]
benzyn
X
R1
C.
Meta constraint
Nu
R2 = H, OMe, F
R1
1
R1
or tether with E
site-selective
halogenation
E
Pd/NBE
X
2
R2
4
R2
R2 is sizable
meta
problematic
(NBE-containing
side products)
R2
D.
This work
R1
R1
O
X
Nu
E
Pd/L, base
Nu-
Me
N
E
LG
NBE*
H
NBE*
R2
R2
diverse
E = alkyl, amino, acyl
Nu = alkenyl, H, aryl, CN, Me
The palladium/norbornene (Pd/NBE) cooperative catalysis, originally discovered by Catellani,6 has
emerged as a useful approach for site-selective arene functionalization.7 In principle, electrophilic halogenation of
common 1,4-disubsitituted arenes followed by the Catellani-type reaction could afford the desired 1,2,3,4-
tetrasubstituted arenes in a regioselective manner. However, such an approach has been held back largely due to
an intrinsic limitation of the Pd/NBE catalysis, namely the “meta constraint” (Scheme 1C).8 That is, substitution
at the C4 meta position (R2) can greatly hamper the efficiency of the ortho functionalization and often lead to
NBE-attached side products or direct ipso substitution, with a few exceptions such as using tethered electrophiles
(pioneered by Lautens9) or very small meta substituents10 (e.g. F and OMe). The “meta constraint” can be quite
significant: even a methyl group11 or a moderately strong electron-withdrawing group, such as an ester moiety, at
the C4 position could greatly inhibit the Catellani pathway.8 Therefore, to enable the Pd/NBE catalysis to be a
general and useful method for constructing 1,2,3,4-tetrasubstituted arenes from readily available 1,4-
disubsitituted arenes, the meta constraint ought to be addressed. Herein, we describe the initial development of a
unique catalytic system that can tolerate meta substituents with various steric and electronic properties in the
2
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Journal of the American Chemical Society
Pd/NBE catalysis. This approach provides a convenient entry to diverse 1,2,3,4-tetrasubstituted arenes in a
modular fashion.
1
2
3
4
5
6
7
8
9
Compared with regular haloarene substrates without a meta substituent (R2 = H), the challenge of using
the C4 meta-substituted ones is three-fold (Scheme 2). First, formation of the key aryl-norbornyl-palladacycle
(ANP) intermediate (II) would be more difficult due to the increased steric hindrance to access the ortho C−H
bond via concerted metallation deprotonation (CMD),8 which could lead to an early ipso termination with the
nucleophile. Second, even though the ortho metallation could be successful, the bulkiness around ANP would
hinder its reaction with the electrophile (E-X), which would promote direct reductive elimination to form the
norbornyl-benzocyclobutene side products.12 Third, the reductive elimination from the proposed Pd(IV)
intermediate III could have a selectivity issue due to the eclipsing interaction between the meta substituent and
the E moiety, which could introduce the E group to the norbornyl part.13
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Scheme 2. Challenges for overcoming the “meta constraint”
R1
R1
Nu
X
E
R2
R1
R1
R2
PdII
E
PdII
Nu
Pd(0)
R2
R2
+

R1
R1
R1
- HX
E
X
PdIV
PdII
II
PdII
X
R2
E
R2
(ANP)
R2
I
III
pitfalls
Nu
R1
R1
R1
E
Nu
(or ipso)
R2
four-membered ring
R2
undesired selectivity
R2
early termination
RESULTS AND DISCUSSION
To seek solutions to the meta constraint, it was clear that the steric and electronic properties of the X-type
and L-type ligands on the Pd, as well as the structure of the NBE cocatalyst, would play critical roles. To explore
the feasibility, substrate 1a bearing a bulky isopropyl group at the C4 position meta to the iodide was chosen as
the standard substrate, and ortho alkylation/ipso Heck reaction was chosen as the model reaction.6,14 Not
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surprisingly, under the previously reported conditions, only a trace amount of the desired product 4a was
observed. After carefully examining various phosphine ligands and additives, 19% yield of 4a was afforded with
simple NBE (N1) and the direct Heck product 4a’ and the corresponding norbornyl benzocyclobutene was found
as the major side product. The structurally modified NBEs were then investigated. Interestingly, the C5-amide-
substituted NBE (N2) gave a notably better performance,15 though the exact reason is unclear. In contrast, C1- or
7-subsituted NBEs (N3 and N4) were ineffective.16 For C2-substituted NBEs, we anticipated that electronic effect
could have a pronounced impact on their reactivity (vide infra, Table 4). While NBEs with cyano (N5),
trifluoromethyl (N6), methyl ketone (N7), and carboxylic acid (N8) groups at 2-positions were not effective, the
methyl ester substituted NBE (N9), pioneered by the Yu group,17 gave the desired product in 40% yield, albeit
still favoring the direct Heck product 4a’ in 55% yield. Gratifyingly, amide-substituted NBEs (N10-N12)18 were
found more reactive and selective for the desired product. While the N-methyl amide-substituted NBE (N11)
proved to be optimal, the free NH2 and N-iPr amide-derived NBEs (N10 and N12) were also effective. The N-
phenyl amide-substituted NBE (N13) would lead to undesired C−H activation on the phenyl ring, while bulky
tertiary amides (N14−N17) were less reactive.
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2
3
4
5
6
7
8
9
10
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Table 1. NBE Effect for the meta-Substituted Aryl Iodidea,b
CO2Me
CO2Me
OMe
OMe
OMe
Pd(MeCN)2Cl2, Ph-DavePhos
I
CO2Me
N
5-CF3-2-pyridinol,
1,4-dioxane: toluene (1:1)
Cs2CO3, 100 o
nBu
I
+
+
nBu
Me
C
Me
Me
1a
Me
Me
4a'
Me
7
2a
3a
4a
nC7H15
OBn
1
2
1
2
CN
5
CONHMe
N1
N2
: 48%
N3
N4
4a
N5
4a
: 20%
4a'
: 14%
4a
4a
4a
: 19%
4a'
: 8%
: n.d.
4a'
4a'
4a'
: 13%
: 13%
: 46%
: n.d.
O
O
O
O
CF3
O
NH2
O
Me
H
CH3
N10
N9
: 40%
N6
N7
N8
4a
: 4%
4a'
: 26%
4a
4a
: 63%
4a
4a
: n.d.
: 1%
4a'
4a'
: 15%
: 55%
4a'
4a'
: 80%
: 60%
O
O
O
O
iPr
N
N
Me
N
N
Ph
Me
H
H
H
Me
N11
4a
N12
4a
N13
4a
N14
4a
: 75%
: 73%
: 2%
: 3%
4a'
4a'
4a'
4a'
: 70%
: 18%
: 16%
: 25%
O
O
O
N
N
N
Et
Et
N16
4a
: 67%
N17
N15
4a
4a'
4a
: 13%
4a'
: 39%
4a'
: 2%
: 76%
: 32%
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a Reaction conditions: 1a (0.10 mmol), 2a (0.30 mmol), 3a (0.15 mmol), Pd(MeCN)2Cl2 (0.01 mmol), Ph-
b
DavePhos (0.01 mmol), N (0.10 mmol), 5-CF3-2-pyridinol (0.02 mmol), Cs2CO3 (0.30 mmol), 100 °C, 16 h.
2
3
4
1
Yield determined by H NMR using 1,1,2,2-tetrachloroethane as the internal standard. Ph-DavePhos: 2-
5
6
Diphenylphosphino-2′-(N,N-dimethylamino)biphenyl.
7
8
9
A series of control experiments were subsequently conducted to understand the role of each reactant
(Table 2). In the absence of the Pd or N11, no desired product was formed (entries 2 and 3). The “ligandless”
conditions gave a much lower yield (entry 4). Pd(MeCN)2Cl2 was slightly more active than Pd(OAc)2 (entry 5),
while Ph-DavePhos was more effective than the commonly used P(2-furyl)3 (entry 6). Consistent with the
previous studies,14,18 the use of a weaker base decreased the yield (entry 7). 5-Trifluoromethyl-2-pyridinol,
previously employed by Yu to promote CMD processes,19 is more efficient than pivalic acid (entries 8 and 9).
Moreover, instead of using a mixed solvent, 1,4-dioxane or toluene alone were not as efficient (entries 10 and
11). While stoichiometric NBE was used to suppress the competing direct Heck reaction, 80 mol% of N11 can be
recovered. Reduction of the N11 loading to 50 mol% still afforded a 59% yield of the desired product (entry 12).
10
11
12
13
14
15
16
17
18
19
20
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22
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57
58
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Table 2. Control Experimenta,b
O
N
Me
CO2Me
CO2Me
OMe
OMe
OMe
H
N11
I
CO2Me
Pd(MeCN)2Cl2, Ph-DavePhos
5-CF3-2-pyridinol
nBu
I
+
+
nBu
(%)
1,4-dioxane: toluene (1:1)
Cs2CO3, 100 o
C
Me
Me
Me
Me
4a'
Me
Me
"standard" conditions
1a
2a
3a
4a
4a
4a'
(%)
Yield of
Yield of
Entry
Variations from the "standard" conditions
75c
1
2
3
4
5
6
7
8
9
none
18
n.d.
80
33
15
26
36
45
18
32
26
29
n.d.
n.d.
30
no Pd(MeCN)Cl2
N11
no
no Ph-DavePhos
Pd(OAc)2 instead of Pd(MeCN)2Cl2
P(2-furyl)3 instead of Ph-DavePhos
K2CO3 instead of Cs2CO3
no 5-CF3-2-pyridinol
69
26
40
n.d.
24
PivOH instead of 5-CF3-2-pyridinol
1,4-dioxane alone
64
10
11
12
27
toluene alone
59
N11
50 mol% of
a Reaction conditions: 1a (0.10 mmol), 2a (0.30 mmol), 3a (0.15 mmol), Pd(MeCN)2Cl2 (0.01 mmol), Ph-
DavePhos (0.01 mmol), N11 (0.10 mmol), 5-CF3-2-pyridinol (0.02 mmol), Cs2CO3 (0.30 mmol), 100 °C, 16 h. b
1
c
Yield determined by H NMR using 1,1,2,2-tetrachloroethane as the internal standard. 80 mol% of N11 was
recovered after the reaction.
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Table 3. Substrate Scopea
1
2
3
4
5
R3
R1
R1
O
R3
I
"standard" condition
+
R4
I
+
N
Me
R4
H
R2
R2
N11
6
1
2
3
4
7
Aryl halide scope
8
9
E
E: CO2Me
OMe
E
E
OMe
OMe
E
E
E
E
OMe
OMe
OMe
OMe
Me
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
nBu
nBu
nBu
Me
nBu
nBu
OMe
nBu
nBu
Me
O
N
Me
4b
O
Me
b
b
4f
4g
, 51%
, 49%
4e
, 80%
, 78%
4a
4c
4d
, 73%
, 73%
, 83%
BnO
E
E
E
E
MOM
E
E
OMe
OMe
OMe
O
OMe
nBu
nBu
nBu
Me
nBu
nBu
Me
, 74%
nBu
Me
F
4j
N
Cl
Br
Me
Me
4m
, 74%
4k
, 75%
4l
4i
, 86%
, 80%
4h
, 50%
O
E
E
Me
E
TBSO
E
OMe
H
nBu
H
H
E
nBu
O
nBu
nBu
Me
nBu
Me
4n
MeO
O
4r
, 86%
b
4q
, 92%
nBu
, 73%
4o
4p
, 52%
, 82%
E
E
E
nBu
E
nBu
when R1 = H
nBu
R3
R4
I
nBu
OMe
nBu
nBu
nBu
R4
Me
OMe
4u
R2
O
R2
Me
Me
c
c
c
b,c
4s
4t
4v
, 65%
, 76%
, 80%
, 91%
Olefin and alkyl iodide scope
O
O
O
tBu
CN
OtBu
OMe
OMe
Me
OMe
OMe
OMe
N
OMe
N
H
nBu
Me
nBu
Me
nBu
nBu
Me
nBu
Me
nBu
Me
Me
Me
Me
Me
Me
4x
Me
Me
4aa
4ab
, 58%
, 58%
4w
4z
, 70%
, 68%
, 62%
4y
, 57%
E
E
E
E
OMe
OMe
OMe
OMe
E: CO2Me
E
Me
N
I
Cl
Me
Me
Me
Me
Me
Me
4ac
Me
Me
4ad
Me
4ae
Me
Me
Me
, 72%
, 55%
, 73%
4af
, 52%
E
E
OMe
OMe
Br
Cl
Me
Me
Me
4ah
Me
, 71%
4ag
, 75%
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a Reaction conditions: 1 (0.30 mmol), 2 (0.90 mmol), 3 (0.45 mmol), Pd(MeCN)2Cl2 (0.03 mmol), Ph-DavePhos
(0.03 mmol), N11 (0.30 mmol), 5-CF3-2-pyridinol (0.06 mmol), Cs2CO3 (0.90 mmol), 100 °C, 16 h. b K2CO3 was
used instead of Cs2CO3. c Cs2CO3 (1.80 mmol) was used.
1
2
3
4
5
6
7
8
Substrate scope. With the optimized conditions in hand, the scope of iodoarenes was studied first (Table
3). First, various meta substituents with different steric and electronic properties could be tolerated. Not
surprisingly, reduction of steric hindrance from an isopropyl to a methyl group increased the yield (4a−4c).
Phenyl group (4d) and electron-withdrawing moieties, such as nitrile (4e), methyl ester (4f), methyl ketone (4g),
aryl bromide (4h), aryl chloride (4i) and aryl fluoride (4j) were tolerated.20 Strongly electron-donating and bulky
dimethylamine substrate (4k) still afforded a good yield. Besides anisole derivatives, other types of substituents
(4l−4o) at the ortho position (R1) were also suitable. Functional groups, such as MOM, benzyl and TBS ethers,
were compatible. In addition, aryl iodides derived from α-tetralone (4p), phenanthrene (4q), and estrone (4r)
were all competent substrates. Notably, in the absence of ortho substituents, double ortho functionalizations could
take place to afford 1,2,3,4-tetrasubstituted arenes from 3-substituted iodobezenes (4s−4v).
9
10
11
12
13
14
15
16
17
18
19
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22
23
24
25
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34
35
36
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43
44
45
46
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The scope of olefins and electrophiles was examined next. Various Michael acceptors including tert-butyl
acrylate, N-tert-butylacrylamide, acrylonitrile and methylvinyl ketone, and 2-vinylpyridine were smoothly
coupled at the ipso-position (4w−4aa). Less electron-deficient regular styrene (4ab), could also be employed. For
the electrophiles, primary alkyl iodides with different functional groups, such as chloride (4ac), methyl ester
(4ad) and cyclopropane (4ah), can be employed. The use of more sterically hindered alkyl halides led to a
lowered yield (4ae), while secondary alkyl iodides were unreactive under the current condition. It is worthy to
note that methylation (4af) and benzylation (4ag) products could also be obtained using the less reactive
phenyltrimethylammonium salt18 and benzyl chloride, respectively.
Scheme 3. Extension of the reaction scopea
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A.
Different ipso functionalization
OMe
B.
Different ortho functionalization
1
2
3
4
5
6
7
8
CN
CuCN
CO2Me
CO2Me
OMe
5
+
O
N
OBz
nBu
78%
13
3a
Me
Me
N
6
34%
Me
O
OMe
OMe
CO2Me
OB
CO2Me
nBu
2a
I
OMe
14
I
I
3
7
CO2Me
O
O
CO2Me
+
OMe
42%
nBu
Me
Ph
O
Ph
Me
Me
Me
9
15
3a
Me
1c
Ph
1a
8
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
50%
Me
OMe
O
H
16
9
OH
52%
nBu
C.
Use of an aryl bromide
Me
Me
10
CO2Me
OMe
OMe
Br
CO2Me
OH
"standard" condition
OMe
nBu Br
Br
CHO
+
+
Me
57%
Me
51%
11
nBu
Me
Me
Me
Me
4a
17
18
3a
Me
Me
12
a For detailed reaction conditions, see Supporting Information.
To demonstrate the modularity and generality of the synthetic strategy for 1,2,3,4-tetrasubstituted arenes,
different ipso couplings were then investigated (Scheme 3A). In addition to Heck coupling, preliminary success
was obtained with cyanation (6),9c Suzuki quench (8),21 and hydrogenation (10),10c allowing for installation of a
cyanide group, an aryl group or hydrogen, respectively, at the ipso positions. Besides intermolecular reactions, an
intramolecular redox-Heck coupling at the ipso position could also be achieved (12),22 when an allylic alcohol
moiety was tethered with the alkyl iodide. Apart from alkyl electrophiles, ortho amination (14)23 and ortho
acylation (16)15,24 reactions could also be achieved at this stage using O-benzoyl hydroxylamine and benzoyl
anhydride as the electrophiles, respectively (Scheme 3B), albeit with moderate yields. Further, besides using aryl
iodides, a promising level of reactivity has also been observed with aryl bromide 17 as the substrate, in which
alkyl bromide 18 was employed as the electrophile instead under otherwise the standard conditions (Scheme
3C).25
Study of the NBE effect. Elucidation of the effect of substituted NBEs that underlies different activities
may serve as a foundation for discovery of more effective NBE co-catalysts, which in turn could enable new
capability. Hence, a combined experimental and computational investigation was undertaken to understand the
beneficial role of the amide-substituted NBE (N11) in the context of addressing the “meta constraint”. It is worth
mentioning that, similar to the previous finding,18 Ph-DavePhos was first transformed into the corresponding
cyclized phosphafluorene under the reaction conditions, which was the actual ligand and therefore used in our
DFT study.
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When using 2-substituted NBEs as co-catalysts, one major side-product was the direct Heck product
(4a’), which potentially comes from the competitive migratory insertion of methyl acrylate 3a. Thus, we first
investigated the electronic and steric effects of the 2-substituent on the NBE binding and migratory insertion steps
via DFT calculation (Table 4). Previously, when studying the migratory insertion of para-substituted vinylarenes
into palladium-methyl bonds, Brookhart and coworkers found that electron-deficient styrenes bind weaker to Pd,
but meanwhile could facilitate the migratory insertion step.26 This observation parallels the trend found in the
computational study of the NBE insertion step. Strongly electron-withdrawing substituents like CF3 (σp = 0.54)
and CN (σp = 0.66) greatly disfavor the NBE binding (ΔG(Int 1)). The higher energies required to bind these
electron-deficient NBEs lead to higher overall migratory insertion activation barriers with respect to Int 1’
(ΔG‡(TS1)). As a result, these NBEs mainly afforded the direct Heck product (4a’) via TS1’. The same trend was
observed among NBEs with moderately electron-withdrawing substituents, such as CONHMe (σp = 0.36), CO2Me
(σp = 0.45), and COMe (σp = 0.50): the overall insertion (ΔG‡ (TS1)) is the fastest with the least electron-
withdrawing substituent, i.e. CONHMe, due to the more favorable NBE binding. It should be noted that
CONHMe-substituted NBE N11 even gave a lower overall insertion barrier than unsubstituted NBE N1. This is
because, although N11 requires slightly more energy to coordinate with Pd, the rate of the subsequent migratory
insertion step (ΔG‡ (TS1) − ΔG (Int 1)) is significantly accelerated by the weakly electron-withdrawing
substituent. Hence, the CONHMe substituent exhibits the most favorable overall NBE-insertion barrier through
balancing the opposite electronic requirements in the NBE binding and migratory insertion steps.
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 4. Computed NBE Binding Energies and Overall Olefin-Insertion Barriersa
iPr
iPr
I
iPr
L
L
Pd
L
Pd
I
Pd
I
CO2Me
CO2Me
O
CO2Me
O
O
Int 1'
0.0 kcal/mol
TS1'
12.6 kcal/mol
Int 2'
N
‡
CO2Me
TS1
G 
) needs to be < 12.6 kcal/mol
iPr
iPr
I
iPr
L
L
Pd
Pd
L
Pd
I
I
R
O
R
R
O
O
TS1
Int 2
Int 1
NBE
N11
N12
N1
R
ΔG (Int 1) ΔG‡ (TS1)
CONHMe
CONHiPr
H
1.0
1.0
0.1
10.1
10.4
11.8
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N17
N9
CON(CH2)3
CO2Me
COMe
2.4
2.4
3.6
1.0
4.6
4.1
5.8
5.5
11.9
12.1
12.3
12.6
13.2
13.9
14.2
14.6
1
2
3
4
5
6
7
8
N7
N13
N5
CONHPh
CN
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N16
N6
CON(CH2)4
CF3
N14
CONMe2
a
All energies are with respect to Int 1’ and in kcal/mol. Calculations were performed at the M06/SDD-6-
311+G(d,p)-SMD(1,4-dioxane)//B3LYP/LANL2DZ-6-31G(d) level of theory. L is N,N-dimethyl-5-phenyl-5H-
benzo[b]phosphindol-1-amine.
Besides electronic effects, steric effects of the 2-substituent are also expected to play an important role in
dictating the NBE insertion activity. Experimentally, compared to secondary amides (N11 and N12), tertiary
amides (N14−N17) were generally less reactive and gave more direct Heck product 4a’. The computational
results are in agreement with the experimental observations (Table 4). In the migratory insertion transition states
(TS1) with N16 and N14, this steric effect is evidenced by the short distances between the alkyl group on the
amide nitrogen and the norbornyl skeleton (2.01 Å and 2.19 Å, respectively). Such a destabilizing steric effect is
absent in the transition state TS1 for the secondary amide N11 and N12.
iPr
iPr
iPr
L
L
L
I
Pd
I
Pd
I
Pd
O
O
O
Me
Me
O
O
N
O
N
N
H
Me
TS1 N11
TS1 N16
TS1 N14
( )
14.6 kcal/mol
(
)
(
)
10.1 kcal/mol
13.9 kcal/mol
Figure 1. Migratory-insertion transitions states with N11, N16, and N14. L is N,N-dimethyl-5-phenyl-
5H-benzo[b]phosphindol-1-amine.
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2
3
4
5
6
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To understand why amide-substituted N11 is more effective than ester-substituted N9 or simple NBE N1,
the initial reaction rates with these NBEs were measured via kinetic analysis (Figure 2).27 It is clear that ester-
NBE N9 and N1 showed similar initial rates in forming the desired product 4a; however, the one with N11 is 5.7
times faster. On the other hand, these three NBEs showed comparable initial rates for forming the Heck side
product (4a’). Note that besides 4a’, the simple NBE (N1) also gave various other side products (vide supra,
Scheme 2).
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
CO2Me
OMe
nBu
Me
Me
4a
CO2Me
OMe
Me
Me
4a'
Figure 2. Formation of 4a (top) and 4a’ (bottom) over time with different NBEs under the standard
conditions.
To understand the origin of such rate acceleration with amide-substituted N11, a series of kinetic studies
were undertaken to probe the turnover-limiting step (TLS). First, the kinetic order of NBEs showed pseudo zero-
order rate dependence of [N11] or [N9] for forming the desired product 4a, but a negative rate dependence
(inverse first order) for the direct Heck reaction (Table 5). These data suggest that migratory insertion into NBE
N11 or N9 is not the TLS in this reaction, and a higher NBE concentration can suppress the undesired direct Heck
pathway. Second, the rate of reaction shows pseudo zero-order dependencies on [1a] and [5-CF3-2-pyridinol], but
first-order dependence on the concentration of Pd and ligand, [Pd/Ph-DavePhos] (see Supporting Information for
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details). These data indicate that the TLS does not involve oxidative addition of aryl iodide 1a or ligand exchange
with 5-CF3-2-pyridinol. Third, a primary kinetic isotopic effect (KIE) of 2.1 was observed by conducting two
parallel reactions with 1a and 1a-d3 (eq 1 and 2). Such a KIE value is close to those found in other Pd-catalyzed
sp2 C−H activation reactions with CMD (ortho C−H palladation) being the TLS.28
1
2
3
4
5
6
7
8
Table 5. The rate dependence of the NBE concentrationa
9
N11
d[4a’]/d
N9
d[4a’]/d
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
NBE
loading
d[4a]/dt
d[4a]/dt
t
t
100 mol%
50 mol%
25 mol%
0.510
0.483
0.508
0.162
0.250
0.456
0.089
0.101
0.112
0.141
0.256
0.390
a Rates are in mM/min.
CO2Me
OMe
OMe
I
CO2Me
nBu
I
+
kH
+
(1)
nBu
Me
"standard" conditions
Me
Me
Me
1a
2a
3a
4a
CO2Me
OMe
OMe
D
I
CO2Me
D
nBu
I
+
kD
+
(2)
D
nBu
D
D
"standard" conditions
Me
1a
Me
-d3
Me
Me
4a
parallel KIE = kH/kD =2.1
2a
3a
-d2
To understand why the amide-substituted N11 is beneficial during the TLS of the Catellani reaction, the
energy profile of the complete catalytic cycle was then computed by DFT (see Supporting Information for
details). The computational study indicates that the TLS of this reaction is the CMD step (TS2), which is
consistent with the above kinetic results. In line with the comparison experiments in Figure 2, the computed
energy barrier of TS2 is 1.1 kcal/mol lower for N11 than that for N9 (Figure 3). Unexpectedly, analysis of the
transition state structure with N11 revealed a hydrogen bonding interaction between the N−H bond of the amide
moiety and the oxygen of 5-CF3-2-pyridinol that approaches the C−H bond. Such a hydrogen bonding interaction
is evidenced by the short H···O distance (2.24 A) and the bond angle (145.7˚), which fall in the range of favorable
O···H···N hydrogen bonding interactions.29 The NPA (natural population analysis) charge calculations indicated
the oxygen has a negative charge of -0.730 and the hydrogen has a positive charge of +0.410, supporting the
favorable electrostatic interactions in the hydrogen bonding.
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Taken all these mechanistic studies together, the merits of the CONHMe substituent on N11 could be
three-fold: (1) the balanced electronic and steric effect on the NBE scaffold accelerates the 2π insertion step; (2)
the ability to form hydrogen bonding further stabilizes the transition state of the CMD step, which is the TLS of
the reaction; (3) the presence of the C2-substituent inhibits formation of the benzocyclobutene side-product,
consistent with the previous experimental17 and computational30 studies.
2
3
4
5
6
7
8
9
CF3
CF3
CF3
L
I
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
L
L
L
R
N
N
N
iPr
Pd
O
HO
iPr
O
R
R
R
iPr
H
iPr
Pd
Pd
Pd
O
O
O
O
Int 2
Int 3
TS2
Int 4
experimental
computed
CF3
‡
4a
d[ ]/dt
TS2
)
NBE
G (
Me
N
L
N
H
N11
0.510
0.089
O
24.9
26.0
O
H
iPr
Pd
N9
O
TS2 N11
(
)
Figure 3. The computed transition states for the CMD step, which is the TLS. Experimentally determined rates
are in mM/min, and computed activation free energies are in kcal/mol. L is N,N-dimethyl-5-phenyl-5H-
benzo[b]phosphindol-1-amine.
Synthetic application. Finally, the synthetic utility of this strategy was evaluated. Given the wide
presence of 1,2,3,4-tetrasubstituted aryl moieties in various bioactive compounds, we anticipated that this
Catellani reaction-based approach could be useful to streamline syntheses of established target molecules. For
example, tetrahydronaphthalene 24 is a known compound with promising herbicidal activity, which was
originally prepared in 7 steps with a 3% overall yield from benzyl bromide 25.31 Now, compound 24 can be
prepared in one or two steps from commercially available aryl iodide 19 (Scheme 4A). Through an ortho
alkylation followed by intramolecular ipso redox-Heck-relay reaction,22 the corresponding aldehyde (23) was
obtained in 80% yield. The following Tsuji−Wilkinson decarbonylation32 provided the target compound (24) in
an excellent yield. Alternatively, a previously unknown ipso reductive Heck reaction was developed here to
further streamline the synthesis. Using an alkene-tethered alkyl iodide (20) as the coupling partner, 2-propanol
was found to be effective to terminate the final alkyl-Pd(II) intermediate, directly leading to the desired tert-alkyl-
substituted arene product (24).
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Scheme 4. Applications in the synthesis of bioactive compounds
1
2
3
4
5
6
7
8
9
OMe
A
OH
Me
CHO
Rh(PPh3)3Cl
90%
this method
Br
80%
22
Me
two steps, 72% yield
O
OMe
23
OMe
Me
OMe
Me
Me
OMe
Me
new method
I
[Pd]
I
ortho alkylation/
ipso reductive Heck
+
20
OH
H
Me
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
one step, 53% yield
O
OMe
24
herbicidal activity
O
OMe
O
OMe
Me
19
21
commercially
available
OMe
7 steps, 3% yield
previous route
Br
25
OMe
B
OMe
I
CN
Me
OMe
ref 33
Me
I
CN
Me
this method
one step, 54% yield
+
K4[Fe(CN)6]-3H2O
O
O
Me
N
N
O
O
Me
27
26
commercially
available
Br
OH
Me
28
ROMK channel inhibitor
HO
Me
4 steps, yield not given
previous route
29
O
O
C
OH
OPMB
Me
OPMB
I
Cl
CO2Me
1. ICl
this method
2. PMBCl
+
CO2Me
HO
45%
PMBO
PMBO
45%
(MeBO)3
O
OMe
O
OMe
32
O
OMe
30
31
commercially
available
Me
OMe
OPMB
Me
OH
ref 36
Me
HO
O
DIBAL-H
70%
CHO
HN
Me
OMe
PMBO
HO
O
OMe
33
O
O
O
HO
OH
OMe
Me
9 steps, 24% yield
psymberin
antineoplastic activity
previous route
MeO
34
In the second case, compound 28 is an effective inhibitor of the ROMK (renal outer medullary
potassium) channel and a pharmaceutical candidate for treating cardiovascular diseases. This compound can be
synthesized from a 1,2,3,4-tetrasubstituted aryl intermediate (27) that previously required four steps of
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preparation from a trisubstituted phenol 29.33 Employing the ortho methylation/ipso cyanation chemistry, the
same intermediate was conveniently accessed in a single step (Scheme 4B). In this case, K4[Fe(CN)6]·3H2O9c was
found to be a better cyanide source than CuCN, and simple methyl iodide was more effective for the ortho
methylation9c,34 than the phenyltrimethylammonium salt.
1
2
3
4
5
6
7
8
9
In the third example, psymberin, a cytotoxic natural product isolated from the marine sponge
Psammocinia sp., displays strong antineoplastic activities (Scheme 4C).35 In the existing route, the key penta-
substituted aromatic intermediate (33) was synthesized in 9 steps involving a directed ortho allylation.36 Using the
Pd/NBE catalysis strategy, a four-step sequence was realized to access compound 33. Aryl iodide 31, prepared in
two steps from commericaly available diphenol 30, underwent the ortho alkylation/ipso Suzuki coupling, to
install two alkyl groups at the ortho and ipso positions simultaneously. While product 32 contains two methyl
ester moieties, it was found that the alkyl-derived one was more reactive and can be chemoselectively reduced to
the corresponding aldehyde, which offers a simplified synthetic route to intermediate 33.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
CONCLUSION
In conclusion, a unique amide-substituted NBE has been identified as an effective promoter to overcome
the long-standing “meta constraint” in the Pd/NBE catalysis. Consequently, the selective ortho/ipso
difunctionalization of various aryl halides with sizable meta substituents provides a modular and efficient strategy
for constructing unsymmetrical contiguous tetrasubstituted arenes, which are challenging to be prepared with
conventional approaches. The broad reaction scope and excellent chemoselectivity could make this method
attractive for preparing complex arene-containing compounds with high biological significance. Detailed
experimental and computational studies revealed the roles of the amide substituent on the NBE in facilitating the
migratory insertion and ortho palladation steps, which could have broader implications in the future design of
more effective NBE co-catalysts. Further improvements of the reaction efficiency and selectivity, as well as
expansion of the reaction scope, are ongoing.
ASSOCIATED CONTENT
Supporting Information
Supporting Information Experimental procedures, computational data, kinetic studies, and characterization
data. This material is available free of charge via the Internet at http://pubs.acs.org.
Corresponding Author
gbdong@uchicago.edu
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ORCID
1
2
3
4
5
Jianchun Wang: 0000-0002-3998-8699
Guangbin Dong: 0000-0003-1331-6015
6
7
8
Notes
The authors declare no competing financial interests.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
‡These authors contribute equally to this work.
ACKNOWLEDGMENT
Financial supports from the University of Chicago and NIGMS (1R01GM124414-01A1) are acknowledged. Y.Z. is
supported by a CSC fellowship. X.X. thanks ShanghaiTech University for a fellowship. Calculations were performed
at the Extreme Science and Engineering Discovery Environment (XSEDE) supported by the National Science
Foundation (ACI-1548562).
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Palladium-Catalyzed Coupling Reactions in the Pharmaceutical, Agrochemical, and Fine Chemical Industries.
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(2) Mortier, J. Arene Chemistry: Reaction Mechanisms and Methods for Aromatic Compounds. John
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Biaryls Using Aryne Intermediates. Chem. Soc. Rev. 2016, 45, 6766-6798; (c) Holden, C.; Greaney, M. F. The
Hexadehydro-Diels-Alder Reaction: A New Chapter in Aryne Chemistry. Angew. Chem. Int. Ed. 2014, 53, 5746-
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(5) (a) Suzuki, S.; Segawa, Y.; Itami, K.; Yamaguchi, J. Synthesis and Characterization of
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SYNOPSIS TOC
R1
R1
Nu-
E
O
X
Nu
E
Me
Pd
N
H
R2
R2
unsymmetrical
contiguous
tetrasubstituted
arenes
"meta constraint"
various meta groups tolerated
broad scope
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