Redox-Neutral ortho Functionalization of Aryl Boroxines via Palladium/Norbornene Cooperative Catalysis

Article abstract of DOI:10.1016/j.chempr.2019.02.005

Palladium/norbornene (Pd/NBE) cooperative catalysis, also known as the Catellani reaction, has become an increasingly useful method for site-selective arene functionalization; however, certain constraints still exist because of its intrinsic mechanistic pathway. Herein, we report a redox-neutral ortho functionalization of aryl boroxines via Pd/NBE catalysis. An electrophile, such as carboxylic acid anhydrides or O-benzoyl hydroxylamines, is coupled at the boroxine ortho position, and a proton as the second electrophile is introduced at the ipso position. This reaction does not require extra oxidants or reductants and avoids stoichiometric bases or acids, thereby tolerating a wide range of functional groups. In particular, orthogonal chemoselectivity between aryl iodide and boroxine moieties is demonstrated, which could be used to control reaction sequences. Finally, a deuterium-labeling study supports the ipso protonation pathway. This unique mechanistic feature could inspire the development of a new class of Pd/NBE-catalyzed transformations.Poly-substituted aromatics are ubiquitously found in drugs and agrochemicals. To realize streamlined synthesis, it is highly attractive if functional groups can be site-selectively introduced at unactivated positions with common arene starting materials. Here, a method is developed to directly introduce acyl and amino groups at unactivated ortho positions of readily available aryl boron compounds. Compared with the known ortho functionalization approaches, this method does not require stoichiometric bases, external oxidants, or reductants. Consequently, the reaction is chemoselective: a wide range of functional groups, including highly reactive aryl iodides, can be tolerated. The primary innovation lies in the use of a proton to terminate the ipso aryl intermediate and regenerate the active palladium catalyst. This unique mode of reactivity in the palladium/norbornene catalysis should open the door for developing new redox-neutral methods for site-selective arene functionalization.A redox-neutral ortho functionalization of aryl boroxines via palladium/norbornene cooperative catalysis is developed. The ortho amination and acylation are achieved with carboxylic acid anhydrides and O-benzoyl hydroxylamines as an electrophile, respectively, whereas protonation occurs at the ipso position. This transformation avoids using either extra oxidants and reductants or stoichiometric bases and acids. In addition, orthogonal chemoselectivity between aryl iodide and boroxine moieties is demonstrated for pathway divergence.

Full text of DOI:10.1016/j.chempr.2019.02.005

Article
Redox-Neutral ortho Functionalization of Aryl
Boroxines via Palladium/Norbornene
Cooperative Catalysis
Renhe Li, Feipeng Liu, Guangbin
Dong
gbdong@uchicago.edu
HIGHLIGHTS
First redox-neutral direct ortho
functionalization of aryl boroxines
Proton as the second electrophile
coupled at the ipso position
Avoiding stoichiometric bases in
the Pd/NBE catalysis
Orthogonal chemoselectivity
between aryl iodide and boroxine
moieties
A redox-neutral ortho functionalization of aryl boroxines via palladium/
norbornene cooperative catalysis is developed. The ortho amination and acylation
are achieved with carboxylic acid anhydrides and O-benzoyl hydroxylamines as an
electrophile, respectively, whereas protonation occurs at the ipso position. This
transformation avoids using either extra oxidants and reductants or stoichiometric
bases and acids. In addition, orthogonal chemoselectivity between aryl iodide and
boroxine moieties is demonstrated for pathway divergence.
Li et al., Chem 5, 1–11
April 11, 2019 ª 2019 Elsevier Inc.
https://doi.org/10.1016/j.chempr.2019.02.005

Please cite this article in press as: Li et al., Redox-Neutral ortho Functionalization of Aryl Boroxines via Palladium/Norbornene Cooperative Catal-
ysis, Chem (2019), https://doi.org/10.1016/j.chempr.2019.02.005
Article
Redox-Neutral ortho Functionalization of
Aryl Boroxines via Palladium/Norbornene
Cooperative Catalysis
Renhe Li,1,3 Feipeng Liu,1,2,3 and Guangbin Dong1,4,
*
SUMMARY
The Bigger Picture
Poly-substituted aromatics are
ubiquitously found in drugs and
agrochemicals. To realize
Palladium/norbornene (Pd/NBE) cooperative catalysis, also known as the Catel-
lani reaction, has become an increasingly useful method for site-selective arene
functionalization; however, certain constraints still exist because of its intrinsic
mechanistic pathway. Herein, we report a redox-neutral ortho functionalization
of aryl boroxines via Pd/NBE catalysis. An electrophile, such as carboxylic acid
anhydrides or O-benzoyl hydroxylamines, is coupled at the boroxine ortho
position, and a proton as the second electrophile is introduced at the ipso posi-
tion. This reaction does not require extra oxidants or reductants and avoids stoi-
chiometric bases or acids, thereby tolerating a wide range of functional groups.
In particular, orthogonal chemoselectivity between aryl iodide and boroxine
moieties is demonstrated, which could be used to control reaction sequences.
Finally, a deuterium-labeling study supports the ipso protonation pathway.
This unique mechanistic feature could inspire the development of a new class
of Pd/NBE-catalyzed transformations.
streamlined synthesis, it is highly
attractive if functional groups can
be site-selectively introduced at
unactivated positions with
common arene starting materials.
Here, a method is developed to
directly introduce acyl and amino
groups at unactivated ortho
positions of readily available aryl
boron compounds. Compared
with the known ortho
functionalization approaches, this
method does not require
INTRODUCTION
stoichiometric bases, external
oxidants, or reductants.
Site-selectivity control still represents an ongoing quest in organic synthesis.1,2
Especially, site-selective functionalization of arenes has been playing a key role in
preparing aromatic moieties ubiquitously found in drugs and agrochemicals.
Recently, the palladium/norbornene (Pd/NBE) cooperative catalysis, pioneered by
Catellani3 and Lautens,4 has emerged as a useful set of tools to access poly-
substituted arenes. In a typical Catellani reaction, a nucleophile and an electrophile
are coupled at the ipso and ortho positions, respectively, through selective reactions
with the aryl-NBE palladacycle (ANP) intermediate (Scheme 1A).3–33 In particular,
when the nucleophile is a hydride equivalent, a reductive ortho functionalization is
realized. While efficient, the Catellani reaction contains a non-productive process,
which is the removal of the generated acid (HX) with stoichiometric bases. In addi-
tion, the reaction needs to be terminated by a nucleophile or reductant in order
to reform the Pd(0) catalyst. Moreover, the compatibility between the nucleophile
and the electrophile is an inevitable concern, and typically, only masked or weak nu-
cleophiles are suitable. Very recently, Zhang34 and Zhou35 concurrently reported a
novel arylboronic-acid-based Catellani reaction also through coupling an electro-
phile-nucleophile pair, but stoichiometric bases and oxidants were still required
(Scheme 1B).
Consequently, the reaction is
chemoselective: a wide range of
functional groups, including
highly reactive aryl iodides, can be
tolerated. The primary innovation
lies in the use of a proton to
terminate the ipso aryl
intermediate and regenerate the
active palladium catalyst. This
unique mode of reactivity in the
palladium/norbornene catalysis
should open the door for
developing new redox-neutral
methods for site-selective arene
functionalization.
Stimulated by these intrinsic constraints in the Catellani reaction, we felt it could be
attractive to develop a redox-neutral arene ortho functionalization, in which an aryl
nucleophile (e.g., aryl boron compounds) could be coupled with two electrophiles
Chem 5, 1–11, April 11, 2019 ª 2019 Elsevier Inc.
1

Please cite this article in press as: Li et al., Redox-Neutral ortho Functionalization of Aryl Boroxines via Palladium/Norbornene Cooperative Catal-
ysis, Chem (2019), https://doi.org/10.1016/j.chempr.2019.02.005
A
B
R
R
+
Nu
R
E
R
+
Nu
E
I
Nu
E
B(OH)2
H
Nu
E
Pd(0)/NBE
base
when Nu
reductive
= H
Pd(II)/NBE
oxidative
FG
FG
FG
FG
base/oxidant
H
Pd(0)/NBE
base
oxidant
PdX2/NBE
base
Pd(0)
Nu
Pd(0)
Nu
R
R
R
NBE
R
NBE
Pd
E
Pd
E
X
E
X
FG
FG
PdII
PdII
ANP
E
ANP
base•HI
non-productive
producess
HI
+
base
stoichiometric
C
D
R
R
E'
this work ( E' = H)
E
+
M
E'
R
BO
Pd(II)/NBE
R
redox-neutral
E
FG
FG
H
E
ortho
acylation
amination
E
H
Pd(II)/NBE
cat. base
*
*
FG
FG
H
PdX2
PdX2/NBE
E'
boroxine
E: -COR'
or NR'2
R
PdX2/NBE
HX
R
NBE
PdX2
HX
Pd
X
E
FG
R
PdII
R
NBE
E
Pd
ANP
E
X
FG
PdII
E
ANP
Scheme 1. Palladium/Norbornene Cooperative Catalysis
without the need for stoichiometric bases or oxidants (Scheme 1C). Mechanistically,
after the ortho functionalization with ANP followed by NBE extrusion, the resulting
aryl-Pd(II) species could then react with another electrophile (instead of a nucleo-
phile or reductant) to regenerate the Pd(II) catalyst. Seminal work by Lautens has
shown that such an aryl-Pd(II) species could attack an adjacent carbonyl group,
but this has been limited to an intramolecular transformation.15 Clearly, many chal-
lenges can be envisioned with this redox-neutral strategy, including the difficulty of
controlling site-selectivity and the choice of suitable electrophiles. Thus, at this pre-
liminary stage, we have been focused on a simplified system with one electrophile
being a proton source (Scheme 1D).31–33 In this reaction, the acid generated during
the ANP formation could be re-coupled at the ipso position, which leads to a net
proton swap. Herein, we describe our initial development of Pd/NBE-catalyzed
redox-neutral acylation and amination using aryl boroxines as substrates, which
directly introduces a functional group at the arene ortho position without extra
stoichiometric oxidants or reductants.
RESULTS AND DISCUSSION
1Department of Chemistry, University of Chicago,
Chicago, IL 60637, USA
The challenges for developing such a redox-neutral transformation are two-fold.
First, given that the aryl-Pd(II) intermediate formed after the NBE extrusion is typi-
cally less nucleophilic, protonation of such a species could be difficult.36 Second,
transmetalation of aryl boronates is generally promoted by basic conditions, while
the final protonation step requires the presence of an acid. Hence, the compatibility
of these two steps could be another concern. We hypothesized that the key for the
success of this reaction would be to discover a catalyst system that can promote
2Department of Applied Chemistry, China
Agricultural University, Beijing 100193, China
3These authors contributed equally
4Lead Contact
*Correspondence: gbdong@uchicago.edu
https://doi.org/10.1016/j.chempr.2019.02.005
2
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Please cite this article in press as: Li et al., Redox-Neutral ortho Functionalization of Aryl Boroxines via Palladium/Norbornene Cooperative Catal-
ysis, Chem (2019), https://doi.org/10.1016/j.chempr.2019.02.005
Pd(TFA)2 (10 mol%)
Me
AsPh3 (30 mol%)
Me
NBE (20 mol%)
K2CO3 (15 mol%)
CuI (30 mol%)
O
O
BO
1/3
+
Ph
Ph
O
Ph
BQ (10 mol%), 4Å MS
toluene, 100 oC, N2
"standard" condition
3
O
1a
2a
3aa
Yielda
65%
0%
Entry
Change from the "standard" condition
1
2
none
w/o Pd(TFA)2
w/o NBE
0%
3
w/o AsPh3
0%
4
5
43%
12%
6%
Pd(OAc)2 instead of Pd(TFA)2
PPh3 instead of AsPh3
6
7
(2-furyl)3P instead of AsPh3
w/o BQ
32%
53%
51%
8
w/o CuI
9
w/o K2CO3
10
11
12
13
14
43%b
0%
w/o 4Å MS
H2O (1.0 equiv) instead of 4Å MS
52%c
0%
commerical "ArB(OH)2" instead of (ArBO)3
ArBpin instead of (ArBO)3
Figure 1. Control Experiments for ortho Acylation with 2-Tolylboroxine
The reaction was run with 0.2 mmol 1a (monomer of boroxine) and 0.4 mmol 2a in 4 mL toluene for 14 h.
aDetermined by 1H NMR analysis using 1,1,2,2-tetrachloroethane as the internal standard.
bToluene after freeze-pump-thaw treatment was used.
cPurchased from Combi-Blocks, containing 28% free 2-tolylboronic acid determined by 1H NMR analysis.
both transmetalation and protonation. The use of arsine-type ligands caught our
attention because first, AsPh3 is known to promote fast transmetalation in Stille re-
actions,37 and second, AsPh3 was also found to be the most efficient ligand in our
previous meta CꢀH arylation reaction,32 which requires facile de-protonation and
re-protonation at the arene ortho position.
To test this hypothesis, we studied ortho acylation as the model reaction; 2-tolylbor-
oxine (1a) and benzoic anhydride (2a) were employed as the initial model
substrates. After careful evaluation of various reaction parameters (Tables S1–S4),
the Pd(TFA)2/AsPh3 combination indeed provided the desired ortho acylation
product 3aa in 65% yield (Figure 1, entry 1). No direct ipso substitution between
the aryl boroxine and benzoic anhydride was observed in this case. A number of
control experiments were subsequently carried out. First, the Pd salt, NBE, and
AsPh3 were all essential to this reaction (Figure 1, entries 2–4). Other Pd(II)
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ysis, Chem (2019), https://doi.org/10.1016/j.chempr.2019.02.005
Me
Me
O
O
BO
"standard" condition
1/3
+
Ar
Ar
O
Ar
3
O
3aa-3as
1a
2a-s
Me
Me
Me
F
Me
F
F
F
O
O
O
O
3aa, 65%
3ab, 74%
Me
3ac, 67%
Me
3ad, 62%
Me
Me
Cl
I
Cl
Br
O
O
O
O
3ae, 66%
3af, 66%
3ah, 31%
3ag, 61%
Me
Me
Me
Me
Me
CF3
CO2Me
O
Me
O
O
O
3ak, 48%
3aj, 53%
3ai, 63%
3al, 52%
Me
Me
Me
OMe
Me
OMe
MeO
Bpin
OMe
O
MeO
O
O
O
3ao, 37%
3ap, 41%
3an, 51%
3am, 58%
Me
Me
Me
Me
Me
S
Ph
Fe
O
O
O
O
3ar, 33%
3as, 50%
3aq, 32%
3at, 60%
Figure 2. Substrate Scope with Respect to Anhydrides
The reaction was run with 0.3 mmol 1a and 0.6 mmol 2a in 4 mL toluene for 14 h.
4
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Please cite this article in press as: Li et al., Redox-Neutral ortho Functionalization of Aryl Boroxines via Palladium/Norbornene Cooperative Catal-
ysis, Chem (2019), https://doi.org/10.1016/j.chempr.2019.02.005
R
R
O
O
2
BO
1
R1
3
4
"standard" condition
R1
1/3
Ar
O
Ar
Ar
+
except wtih
7.5 mol% Pd(TFA)2
22.5 mol% AsPh3
6
Ar = p-FC6H4
3
O
5
1b-s
3bb-3sb
2b
Et
Ph
F
F
F
O
O
O
3db, 47%a
3bb, 53%
OMe
3cb, 26%
Me
Me
F
F
F
Ph
Me
O
O
O
3eb, 48%a
3gb, 69%
3fb, 60%
Me
Me
Me
F
F
F
Me2N
F
MeO2C
O
O
O
O
3hb, 58%
3jb, 54%a
3ib, 48%
Me
Me
Me
F
F
F
F
OMe
MeN
Cl
O
O
O
O
3kb, 62%a
3lb, 64%
3mb, 70%
Me
Me
Me
MeO2C
F
NC
F
MeO
F
O
O
O
3ob, 51%
3pb, 36%a
3nb, 62%
O
Me
Me
O2N
F
F
F
O
F
O
3qb, 33%a
3sb, 45%
3rb, 42%
Figure 3. Substrate Scope with Respect to Aryl Boroxines
The reaction was run with 0.3 mmol 1b-s and 0.6 mmol 2b in 4 mL toluene for 14 h.
a10 mol % of Pd(TFA)2 and 30 mol % of AsPh3 was used.
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ysis, Chem (2019), https://doi.org/10.1016/j.chempr.2019.02.005
(0.60 D)
D
D
D/H
O
D
D
BO
D
D
D
D
D
D
D
"standard" condition
(1)
2b
+
1/3
except wtih
15 mol% Pd(TFA)2
45 mol% AsPh3
20 mol% BQ
D
F
D
3
3sb-d
1s-d
36%
Me (0.38 D)
D/H
Me
F
BO
"standard" condition
(2)
1/3
+
2b
except with
D2O (2.0 equiv)
3
O
3ab-d
1a
32%
Scheme 2. Deuterium-Labeling Studies
precatalysts or phosphine-based ligands were less efficient (Figure 1, entries 5–7). It
is noteworthy that whereas the majority of the prior Pd/NBE-catalyzed reactions
used a high loading or excess NBE,5–10 only 20 mol % NBE was sufficient in this
reaction. A catalytic amount of benzoquinone could improve the reaction yield (Fig-
ure 1, entry 8), which most likely serves as a Pd(0) scavenger or a p-ligand38–40 to pre-
vent catalyst decomposition. A catalytic amount of CuI and K2CO3 also enhanced
the yield, though their roles were not critical (Figure 1, entries 9 and 10).41 One hy-
pothesis is that a catalytic amount of carbonate base may facilitate the transmetala-
tion of boroxines or promote the concerted metalation deprotonation step to form
the ANP. The reaction was sensitive to water, and adding molecular sieves signifi-
cantly increased the yield (Figure 1, entries 11 and 12). Use of aryl boroxines instead
of boronic acids was beneficial, though the commercial ‘‘boronic acid’’ that contains
ꢁ28% ArB(OH)2 and ꢁ72% boroxine (Figures S1–S3) still afforded the desired prod-
uct in 52% yield (Figure 1, entry 13). In contrast, the corresponding pinacol-derived
substrate was not reactive, most likely because of its difficulty in the transmetalation
step (Figure 1, entry 14).42
The scope of the reaction with respect to the acyl part was examined first (Figures 2
and S4–S47). Anhydrides with electron-donating and electron-withdrawing groups
all afforded the desired ortho acylation products in moderate to good yields.
Generally, the more electron-deficient aromatic anhydrides (e.g., 3ab and 3ae)
gave slightly higher yields than the ones richer in electrons, probably because of their
enhanced reactivity toward the ANP intermediate. One important feature is that a
number of functional groups, including aryl fluoride (3ab–3ad), chloride (3ae and
3af), bromide (3ag), iodide (3ah; vide infra Schemes 3 and 4), trifluoromethyl (3ai),
ester (3aj), and anisole moieties (3am–3ao), were tolerated. The ortho-substituted
aromatic anhydrides (3ak and 3ao) were competent substrates. It is noteworthy
that pinacol boronates were compatible (3ap), which could serve as a handle for
further functionalization. In addition, ferrocene- (3aq) and thiophene-derived ketone
products (3ar) could be isolated in moderate yields. Encouragingly, aliphatic carbox-
ylic acid anhydrides also proved to be suitable coupling partners (3as and 3at).
Next, the scope of the aryl boroxines was explored. Notably, a lower Pd loading
(7.5 mol %) was applied in these reactions (Figures 3 and S48–S101). Substitutions
6
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Me
A
Me
I
F
"standard" condition
Me2N
Me
+
except with
4a (1.0 equiv)
BO
O
O
1/3
4a, fully recovered
3ab, 68%
3
1a
+
O
O
N
H
Me
I
Ar
O
Ar
F
"standard" condition
Ar = p-FC6H5
N
H
+
H
except with
4b (1/3 equiv)
2b
O
O
O
H
3ab, 55%
4b, fully recovered
B
Me
Me
Br
"standard"
condition
Br
F
BO
2b
+
47%
75%
reductive
ortho
amination
Me
O
1t
3tb
F
R2N
Me
O
Me
"standard"
condition
I
F
4uba
76%
I
BO
2b
+
NR2 = morpholino
63%
O
3ub
1u
Scheme 3. Tolerance of Aryl Iodide and Bromide Moieties
at the C2–C5 positions of aryl boroxines could all be tolerated. For the para-
substituted aryl boroxines, aryl fluoride (3hb), chloride (3lb), ester (3ib), amide (3jb),
Weinreb amide (3kb), phenyl (3gb), and alkyl groups (3fb) were compatible. In addi-
tion, aryl boroxines that contain an electron-donating or electron-withdrawing substit-
uent smoothly provided the ortho acylation products in moderate to good yields.
Although the trend of the electronic effect with the aryl boroxine substrates was not
obvious, those bearing a strong electron-withdrawing group at the C3 position (3pb
and 3qb) typically gave lower yields. Moreover, a naphthalene-derived substrate
(3sb) also provided the desired ketone product.
To gain some mechanistic insight into this reaction, deuterium-labeling studies were
performed (Scheme 2; Figures S102 and S103). When the fully deuterated substrate
1s-d reacted with anhydride 2b, the desired product (3sb-d) was isolated with
Chem 5, 1–11, April 11, 2019
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ysis, Chem (2019), https://doi.org/10.1016/j.chempr.2019.02.005
Me
redox-neutral
"B first, then I"
F
ortho
acylation
O
I
68%
ortho
61%
Me
[B] = B(O)
amination
O
7
Me
[B]
I
F
O
R2N
O
NR2 = morpholino
O
[B] = Bpin
[B] = B(O)
5
6
8
99%
Me
[B]
redox-neutral
ortho
acylation
ortho
amination
[B] = Bpin
64%
R2N
O
60%
"I first, then B"
[B] = Bpin
9
73%
[B] = B(OH)2 10
Scheme 4. Controlling the Reaction Sequence Enabled by Orthogonal Chemoselectivity
60% deuterium incorporated at the ipso position (Scheme 2, Equation 1). The
erosion of deuterium incorporation was possibly due to the H-D exchange with
adventitious water in the reaction system. To examine the possibility of the H-D
exchange, we conducted a reverse control experiment. Using regular 2-toylboroxine
1a as the substrate, we ran the standard reaction in the presence of 2.0 equiv of D2O
(Scheme 2, Equation 2). Although the reaction still contained a significant amount of
molecular sieves, 38% deuterium was nevertheless observed as the ipso position of
the product. These results are consistent with an ipso protonation pathway pro-
posed in Scheme 1D.
One potential merit of aryl-boroxine-mediated reactions is the compatibility of aryl
iodide moieties,35 which are otherwise highly reactive under the typical Pd/NBE
catalysis conditions (Scheme 3A).5–10 First, in the presence of aryl iodide 4a, ortho
acylation of 2-tolylboroxine 1a still proceeded selectively with a full recovery of un-
reacted aryl iodide 4a. Encouragingly, a more complex aryl iodide (4b) derived from
strychnine remained intact under the reaction conditions, whereas the ortho acyla-
tion with boroxine 1a provided the desired product (3ab) in 55% yield.43 In addition,
substrates bearing halogens and boroxines on the same aromatic ring were tested
(Scheme 3B; Figures S128–S140). Gratifyingly, both the aryl bromide (1t) and iodide
(1u) groups survived under the standard ortho acylation conditions; such compati-
bility allows for convenient sequential functionalization of the arene substrates.
Encouraged by the unique chemoselectivity in the aryl-boroxine-mediated reac-
tions, orthogonal reactivity between aryl iodide (I) and boroxine (B) moieties was
next explored; if successful, this would provide a convenient way to control the
8
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R
R
X
BO
R1
Pd(OPiv)2/P(OPh)3
R1
1/3
+
N
NBE, BQ
CsI, Cs2CO3
toluene, 100 oC
N
3
X
OBz
2
1
4
Me
Me
Me
N
Ph
N
Cl
N
O
O
O
4la, 57%
Me
4aa, 66%a
4ga, 64%
Me
O
MeO
N
N
N
N
O
Boc
4na, 65%
4sa, 62%
4ab, 58%
Figure 4. Substrate Scope of the ortho Amination Reaction
Reaction conditions: 1 (0.5 mmol), 2 (0.2 mmol), Pd(OPiv)2 (20 mol %), P(OPh)3 (40 mol %), NBE (50 mol %), BQ (15 mol %), Cs2CO3 (50 mol %),
CsI (50 mol %), toluene (4 mL), 100ꢂC, 12 h.
aWhen 10 mol % Pd was used instead, 55% isolated yield was observed.
reaction sequence without significant alteration of the substrates (Scheme 4; Figures
S116–S127). Diaryl compound 5 containing both ‘‘I’’ and ‘‘B’’ groups was employed
as the model substrate. First, as expected, the ‘‘B first, then I’’ sequence worked
smoothly, which first gave an ortho acylation on the boroxine site and then an ortho
amination on the iodide site. On the other hand, the ‘‘I first, then B’’ sequence was
also successful: the Pd(0)-catalyzed reductive ortho amination of the aryl iodide
tolerated the pinacol boronate moiety; the resulting intermediate after hydrolysis
then participated in the Pd(II)-catalyzed ortho acylation uneventfully. Thus, without
the need to prepare different substrates, the order of the reaction sequence be-
tween the boroxine and iodide sites could be controlled by different catalytic
systems.
Besides the ortho acylation, preliminary success has also been obtained for
achieving the ortho amination under the redox-neutral conditions (Figures 4 and
S104–S115). O-benzoyl hydroxylamines were found to be suitable electrophiles.
Under modified reaction conditions, the desired ortho amination products could
be obtained in moderate to good yields without the need of reductants.17 Phosphite
ligands, e.g., P(OPh)3, proved to work better than arsine ligands, whereas other
types of ligands were less efficient (Tables S5–S7). To the best of our knowledge,
phosphite ligands have not been used in the Pd/NBE catalysis previously. A piper-
azine-derived electrophile also afforded the desired amination product (4ab) in
58% yield. Efforts on further enhancing the efficiency and scope of this ortho
amination reaction through detailed mechanistic studies are ongoing.
Chem 5, 1–11, April 11, 2019
9

Please cite this article in press as: Li et al., Redox-Neutral ortho Functionalization of Aryl Boroxines via Palladium/Norbornene Cooperative Catal-
ysis, Chem (2019), https://doi.org/10.1016/j.chempr.2019.02.005
In summary, a redox-neutral Catellani-type transformation is developed using aryl
boroxines as substrates. The reaction is enabled by an arsine or phosphite ligand
and a Pd(II) catalyst, showing broad functional-group compatibility. Compared
with the classical reductive Catellani-type reactions, this approach does not require
stoichiometric bases or reductants; in addition, it can tolerate various aryl halide
moieties. Although the efficiency of these methods remains to be further improved,
the unique mechanistic pathway discovered here could have important implications
on developing a new class of Pd/NBE-catalyzed reactions.
EXPERIMENTAL PROCEDURES
Full experimental procedures are provided in the Supplemental Information.
SUPPLEMENTAL INFORMATION
Supplemental Information can be found with this article online at https://doi.org/10.
1016/j.chempr.2019.02.005.
ACKNOWLEDGMENTS
Financial support from the University of Chicago and National Institute of General
Medical Sciences (1R01GM124414-01A1) is acknowledged. F.L. is supported by a
China Scholarship Council fellowship. We thank Dr. Zhe Dong for preliminary inves-
tigation and Mr. Jianchun Wang for checking the experiments.
AUTHOR CONTRIBUTIONS
R.L. discovered the reaction and performed the optimization. R.L. and F.L. per-
formed the substrate scope and application. G.D. directed the project and wrote
the manuscript with input from all authors. All authors analyzed the results and com-
mented on the manuscript.
DECLARATION OF INTERESTS
The authors declare no competing interests.
Received: October 24, 2018
Revised: January 23, 2019
Accepted: February 7, 2019
Published: March 7, 2019
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