Modular ipso/ ortho Difunctionalization of Aryl Bromides via Palladium/Norbornene Cooperative Catalysis

Article abstract of DOI:10.1021/jacs.8b04153

Palladium/norbornene (Pd/NBE) cooperative catalysis has emerged as a useful tool for preparing poly substituted arenes; however, its substrate scope has been largely restricted to aryl iodides. While aryl bromides are considered as standard substrates for Pd-catalyzed cross coupling reactions, their use in Pd/NBE catalysis remains elusive. Here we describe the development of general approaches for aryl bromide-mediated Pd/NBE cooperative catalysis. Through careful tuning the phosphine ligands and quenching nucleophiles, ortho amination, acylation and alkylation of aryl bromides have been realized in good efficiency. Importantly, various heteroarene substrates also work well and a wide range of functional groups are tolerated. In addition, the utility of these methods has been demonstrated in sequential cross coupling/ortho functionalization reactions, consecutive Pd/NBE-catalyzed difunctionalization to construct penta-substituted aromatics and two-step meta functionalization reactions. Moreover, the origin of the ligand effect in ortho amination reactions has been explored through DFT studies. It is expected that this effort would significantly expand the reaction scope and enhance the synthetic potential for Pd/NBE catalysis in preparing complex aromatic compounds.

Full text of DOI:10.1021/jacs.8b04153

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Article
Modular ipso/ortho Difunctionalization of Aryl Bromides
via Palladium/Norbornene Cooperative Catalysis
Zhe Dong, Gang Lu, Jianchun Wang, Peng Liu, and Guangbin Dong
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b04153 • Publication Date (Web): 15 Jun 2018
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Modular ipso/ortho Difunctionalization of Aryl Bromides via Palla-
dium/Norbornene Cooperative Catalysis
Zhe Dong,† Gang Lu,‡ Jianchun Wang,† Peng Liu*‡ and Guangbin Dong*†
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†Department of Chemistry, University of Chicago, Chicago, Illinois 60637, United States
‡Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States
Supporting Information
ABSTRACT: Palladium/norbornene (Pd/NBE) cooperative catalysis has emerged as a useful tool for preparing polyꢀsubstituted
arenes; however, its substrate scope has been largely restricted to aryl iodides. While aryl bromides are considered as standard subꢀ
strates for Pdꢀcatalyzed cross coupling reactions, their use in Pd/NBE catalysis remains elusive. Here we describe the development
of general approaches for aryl bromideꢀmediated Pd/NBE cooperative catalysis. Through careful tuning the phosphine ligands and
quenching nucleophiles, ortho amination, acylation and alkylation of aryl bromides have been realized in good efficiency. Imꢀ
portantly, various heteroarene substrates also work well and a wide range of functional groups are tolerated. In addition, the utility
of these methods has been demonstrated in sequential cross coupling/ortho functionalization reactions, consecutive Pd/NBEꢀ
catalyzed difunctionalization to construct pentaꢀsubstituted aromatics and twoꢀstep metaꢀfunctionalization reactions. Moreover, the
origin of the ligand effect in ortho amination reactions has been explored through DFT studies. It is expected that this effort would
significantly expand the reaction scope and enhance the synthetic potential for Pd/NBE catalysis in preparing complex aromatic
compounds.
flateꢀmediated annulation reaction24 (Scheme 1C), the arene subꢀ
INTRODUCTION
strates in Catellaniꢀtype reactions have been limited to aryl ioꢀ
Polyꢀsubstituted aromatics are ubiquitously found in pharmaꢀ
dides, and use of aryl bromides remained elusive.
ceuticals1, agrochemicals2 and organic materials.3 During the past
decades, crossꢀcouplings4 and nucleophilic aromatic substitutions5
Scheme 1. Arene Functionalization with Aryl Halides
(SNAr) have clearly become indispensable tools for preparing
A. typical cross-coupling reactions
polyꢀfunctionalized arenes from readily available aryl halides
R
R
X
Nuc
Pd(0), Nuc
through introducing a nucleophile at the ipso position (Scheme
1A). While powerful, these approaches typically only introduce
one substituent at one time and the position of the newly installed
functional group (FG) is dictated by the position of the halogen
substituent.6 As a complementary approach for arene functionaliꢀ
zation using aryl iodides, palladium/norbornene (Pd/NBE) coopꢀ
erative catalysis, namely Catellaniꢀtype reactions, allows for viciꢀ
nal difunctionalization of arenes through coupling a nucleophile at
the ipso position and an electrophile at the ortho position simultaꢀ
neously (Scheme 1B).7 It can be envisioned that, through using
different combinations of nucleophiles and electrophiles, a diverse
range of multiꢀsubstituted arene products would be easily obꢀ
tained in one step from simple starting materials, thereby providꢀ
ing a modular approach for ipso/ortho difunctionalization. Howꢀ
ever, there have been some longꢀlasting constraints in Pd/NBE
catalysis that have limited its practical applications in synthesis.
X= I, Br, Cl, F
FG
FG
base
B. Pd/NBE catalysis with aryl iodides
Heck
Alkyne
Hydrogen- Enolate
C-O bond
Selenation
Borylation
Amination
Coupling insertion
ation
coupling
coupling
2000
2004
2005 2006
2016
2009
2014
1997
2001
2009
2012
2005
2015
2004
2018
Cyanation
Suzuki Sonogashira Direct
coupling coupling arylation
Carbene
coupling
Thiolation
1,2-Addition
electrophile
constraint
R
R
Pd/NBE
base
I
Nuc
E
E-X
+
+
HNuc
FG
FG
H
alkylation
2001
aryl iodide
constraint
amination
2015
1997
arylation
2013
acylation
C. previous work: ortho annulation with ArOTf (Lautens)
Important contributions by Catellani, Lautens and others have
demonstrated that, analogous to the cross coupling reactions, a
broad range of nucleophiles can be coupled at the ipso position,
which include Heck coupling,7a,8 Suzuki coupling,9 alkyne inserꢀ
tion,10 Sonogashira coupling,11 cyanation,12 direct arylation,13
amidation14/amination,15 aryl ether formation,16 hydrogenolysis,17
enolate coupling18, 1,2ꢀaddition to carbonyl group,19 vinylation
with hydrazone,20 borylation,21 thiolation,22 and selenation23
(Scheme 1B). However, compared to the highly versatile ipsoꢀ
coupling, the scope of the electrophiles that can be introduced at
the ortho position had been primarily restricted to alkyl and aryl
R1
TMSN
R2
R1
N
R2
Pd/NBE/PPh3
Base
OTf
Cl
FG
+
FG
H
R
D. this work:
Nuc
R1
R2
R1
N
FG
OBz
N
R2
R
R
Br
Nuc
R1
O
O
FG
FG
R1
O
R1
H
HNuc
O
R
halides since the seminal works by Catellani in 19977a and 200110a
In addition, except a single elegant report by Lautens on aryl triꢀ
.
Nuc
R1
R1
X
FG
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Such constraints might be better understood from the proposed
be suitable to afford desired selectivity in the Pd/NBE catalysis. In
catalytic cycle (Figure 1). It starts with oxidative addition of Pd(0)
into the arylꢀiodide bond (Step A), followed by synꢀmigratory
insertion25 into NBE (Step B) and C−H metalation, to generate an
arylꢀNBEꢀpalladacycle (ANP)26 (Step C), which can react with an
electrophile to introduce a FG at the ortho position27 (Step D).
The following deꢀinsertion of NBE through βꢀcarbon (βꢀC) elimiꢀ
nation gives a more sterically hindered arylꢀpalladium species28
(Step E), which disfavors NBE reꢀinsertion compared to the arylꢀ
palladium species from Step A; thereby, it is persistent enough to
be attacked by the nucleophile selectively to furnish the ipso funcꢀ
tionalization and regenerate the Pd(0) catalyst7a (Step F). Thus, to
successfully implement the Pd/NBE catalysis, the electrophile
employed should selectively oxidize or react with the ANP Pd(II)
intermediate instead of the electronꢀrich Pd(0) catalyst (Step G);
on the other hand, the aryl halide substrate must selectively react
with the Pd(0) instead of ANP to avoid selfꢀdimerization (Figure
1B). Given the simultaneous presence of two oxidants (aryl halꢀ
ides and the electrophiles) and two electronꢀrich Pd species (Pd(0)
and ANP), developing new ortho functionalization with expanded
electrophile and aryl halide scopes is not a trivial issue.7g
2013 we reported our preliminary study of developing ortho amiꢀ
nation using Oꢀbenzoyl hydroxylamines as the electrophile29,
illustrating that heteroatoms can be introduced to arene ortho
positions (Scheme 1B). Subsequently, a series of elegant works on
ortho aminationꢀbased different ipso functionalization have been
disclosed.21,30 In 2015, the Liang, Gu and our laboratories concurꢀ
rently described ortho acylation using anhydrides as the electroꢀ
philes.31 Recently, ortho acylation/ipso thiolation with thioesters22
and ortho carboxylation with carbonate anhydrides32 were reportꢀ
ed by Gu and us respectively.
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The challenge of the “aryl iodide constraint” may seem to be
rather surprising, as aryl bromides have proved to be a suitable
coupling partner in the Pdꢀcatalyzed crossꢀcoupling reactions for
more than three decades.33 It is well known that aryl bromides
undergo significantly slower oxidative addition with Pd(0) than
aryl iodides,34 which inevitably increases the chance for the “exꢀ
ternal” electrophile to compete for the oxidation with Pd(0) (Figꢀ
ure 1C). Thus, it is reasonable to imagine the catalytic conditions
that work well for aryl iodides may not work for aryl bromides.35
Hence, fineꢀtuning of the steric and electronic properties of the
Pd(0) catalyst that can selectively accelerate certain steps in the
catalytic cycle, e.g. oxidative addition (Step A) and βꢀC eliminaꢀ
tion (Step E), would become critical to enable the reactions with
aryl bromides.
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From a practicality viewpoint, aryl bromides are generally
cheaper and more accessible than the corresponding aryl
iodides.36 In addition, for heterocycles and complex nature prodꢀ
uct derivatives, the aryl bromides are often more stable towards
light or heat.37 Moreover, availing the Pd/NBE catalysis with aryl
bromides could also enable sequential cross coupling/ortho funcꢀ
tionalization reactions or consecutive difunctionalization with
polyhaloarenes38 (vide infra, Scheme 9). Therefore, efficient and
general methods for ipso/ortho difunctionalization of aryl broꢀ
mides via Pd/NBE catalysis would be attractive.
In this article, we describe systematic efforts for developing
various ortho functionalization reactions with different classes of
electrophiles using aryl bromides as substrates (Scheme 1D). Diꢀ
verse ipso–functionalization with different nucleophiles has also
been exemplified. These methods have allowed for rapid access of
a broad range of polyꢀsubstituted arenes and heteroarenes with
complete control of siteꢀselectivity.
RESULTS AND DISCUSSION
2.1 Ortho amination
In 2004 Johnson and coworkers reported a seminal study on
copperꢀcatalyzed electrophilic amination between Oꢀbenzoyl hyꢀ
droxylamines and organozinc reagent.39 Yu and coworkers deꢀ
scribed the first Pdꢀcatalyzed C−H amination using Oꢀbenzoyl
hydroxylamines in 2011.40 Inspired by these important works, we
found Oꢀbenzoyl hydroxylamines could serve as an excellent
electrophile for Pd/NBE catalysis. In combination with isopropaꢀ
nol as the hydride reductant, the ortho amination/ipso hydrogenaꢀ
tion with aryl iodides was developed in 2013.29 Using different
nucleophiles as quenching reagents, various ipso functionalization
reactions based on ortho amination have been developed (Figure
2), including MizorokiꢀHeck reaction with olefins,30a,f vinylation
with hydrazines,30b Suzuki coupling with aryl and alkyl boronic
acids,30c,g Sonogashira reaction with alkynes,30d,e Miyaura borylaꢀ
tion with diboranes,21 cyanation with cyanides,30h,i ketone αꢀ
arylation with enol equivalents,30j dearomatization with phenols30k
and intramolecular amidation with amides.30l It is clear that the
ortho amination chemistry holds broad applicability and potential
for practical utility;41 however, aryl iodides have been the sole
Figure 1. Mechanistic considerations.
To address the challenge of the “electrophile constraint”, we
hypothesized that electrophiles that have certain coordinating
capability with the more Lewis acidic Pd(II) center at ANP might
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substrates employed in these reactions except a single example in
dppb and DPEphos, gave reasonably good yields. On the contrary,
those with a rigid backbone, such as dppBz, Xantphos and BINAP,
gave NBEꢀattached compound 4a’ as the major product, which
indicates that rigid phosphine ligands likely disfavored NBE exꢀ
trusion. Meanwhile, the flexible backbone may allow one phosꢀ
phine moiety dissociates42 and leaves a vacant site for NBE coorꢀ
dination and subsequent transformations.43 Inspired by the fact
that PCy3 gave higher yield than PPh3, several bidentate trialꢀ
kylphosphines were then tested. Gratifyingly, the dCypb ligand
gave the desired product in 90% yield, though the same trend was
not observed for DPEphos and dppfꢀtype ligands. In addition, the
analogous dCpentapb ligand gave a slightly lower yield, which
later proved to be more efficient for other substrates.
our ortho amination/ipso reduction report using a special electronꢀ
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deficient aryl bromide.29
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Table 1. The Ligand Effect for Ortho Amination with Aryl
Bromidesa
Figure 2. Examples of intermolecular ortho amination of aryl
iodides.
To explore a general ortho amination method with aryl broꢀ
mides, 2ꢀbromoanisole 1a was employed as the model substrate
and the ipso hydrogenation was chosen as the model reaction.
Under the previously reported conditions for aryl iodides,29 poor
mass balance of aryl bromide and low yield of desired product 4a
were observed (Eq 1). Further effort to optimize the reaction idenꢀ
tified that the major sideꢀproduct was NBEꢀattached reduction
compound 4a’ (Eq 2). The formation of 4a’ indicated that βꢀC
elimination of NBE from the Pd(II) center was slower than hyꢀ
dride transfer from the alcohol reductant. We proposed that more
sterically hindered secondary alcohol could significantly decrease
the βꢀhydrogen (βꢀH) elimination speed thereby diminishing the
sideꢀproduct formation. After further examining the reaction conꢀ
ditions, bulky (−)ꢀborneol 3 and 1,4ꢀdioxane was found to be a
better reductant and solvent combination for a balanced reactivity
and selectivity.
a Run on a 0.2 mmol scale (0.1 M) for 14 h with 1.6 equiv of 2a
1
and 1.0 equiv of 3; yields were determined by HꢀNMR using
1,3,5ꢀtrimethoxylbenzene as the internal standard. The number in
parentheses refers to the yield of sideꢀproduct 4a’. For monoꢀ
dentate phosphines, the loading was 22 mol% instead of 11 mol%.
b The corresponding HBF4 salts were used. Cy, cyclohexyl.
Ligand effect: The ligand effect was then carefully investigatꢀ
ed. The yields with monoꢀdentate phosphines were generally
moderate with a significant amount of 4a’ formed (Table 1).
Compared to triaryl phosphines, trialkyl phosphines appear more
selective with minimal 4a’ observed, and by large, electronꢀrich
ligands gave higher yields for the desired product 4a. Extremely
bulky ligands, such as PtBu3, gave a trace amount of desired
product. It is rather surprising that bidentate ligands worked well
in this case, as they are typically less effective than monodentate
ligands when aryl iodides were used as substrates.7e In particular,
bidentate phosphine ligands with a flexible backbone, such as
To investigate the origin of ligands effects on the selectivity beꢀ
tween the desired product 4a and the NBEꢀattached sideꢀproduct
4a’, DFT studies were subsequently carried out (Figure 3). In
particular, we focused on the differences between alkylꢀ and arylꢀ
phosphines as well as the effects of large biteꢀangle bidentate
ligands. Therefore, dCypb, PCy3, and PPh3 were chosen as the
model ligands in the computational study. Given that the NBEꢀ
attached compound 4a’ is the major sideꢀproduct, we computed
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the competing βꢀC elimination pathway (product 4a formation)
Figure 3. Computed barriers of βꢀC elimination and βꢀH eliminaꢀ
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from carboxylate intermediate I and βꢀH elimination (sideꢀproduct
4a’ formation) pathway from alkoxide intermediate II (Figure
3).44
tion from the Pd(II) complexes supported by dCypb, PCy3, and
PPh3 ligands. Activation free energies of βꢀC elimination are with
respect to complex I and activation free energies of βꢀH eliminaꢀ
tion are with respect to complex II. Calculations were performed
at
the
M06/SDD–6ꢀ311+G(d,p)ꢀSMD(1,4ꢀ
dioxane)//B3LYP/LANL2DZ–6ꢀ31G(d) level of theory.
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According to the DFT calculations, the activation energies of
both the βꢀC and βꢀH elimination pathways are affected by the
choice of ligand, and the reactivity trends in these pathways are
different. The βꢀC elimination (TS1a-b, Figure 3A) is promoted
by the use of alkylphosphine ligands (dCypb or PCy3), consistent
with the greater experimental yields of 4a with these ligands.45
Here, the larger cone angle of PCy3 (179°) compared to that of
PPh3 (145°) facilitates the elimination of NBE. This steric effect
is evidenced by the short distance between the PCy3 ligand and
the αꢀhydrogen on the norbornyl group in intermediate I-1b (2.08
Å). A similar steric repulsion is observed in intermediate I-1a
with the monodentate dCypb ligand (2.16 Å), which accounts for
the lower barrier for the βꢀC elimination. It should be noted that
bulkier ligands do not always lead to a lower barrier to the βꢀC
elimination, as PCy3 is slightly less effective than dCypb. In addiꢀ
tion, extremely bulky ligands (e.g. P(tꢀBu)3) actually destabilize
the βꢀC elimination transition state by causing severe repulsions
with the bridgehead hydrogen on the norbornyl group (see Figure
S2 for details). Among the ligands investigated computationally,
the monodentate dCypb is the most effective in βꢀC elimination
due to its optimum steric environment. In other words, if the ligꢀ
and is not sufficiently bulky, the intermediate prior to βꢀC elimiꢀ
nation would be too stable; if the ligand is too sterically hindered,
the transition state for the βꢀC elimination would be of high enerꢀ
gy. Thus, both extreme situations lead to a higher activation barriꢀ
er for βꢀC elimination.
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In the βꢀH elimination pathway, the trend is opposite. The PPh3
ligand was found to exhibit the lowest activation energy, which is
consistent with the relatively high yield of 4a' with this ligand.
Instead of a fourꢀcoordinated Pd(II) intermediate (I), the βꢀH
elimination was found to occur through a threeꢀcoordinated Pd(II)
intermediate (II) (Figure 3B). The use of sterically hindered and
electronꢀrich ligands (dCypb and PCy3) stabilizes the threeꢀ
coordinated alkoxide complex II, and thus slows down the βꢀH
elimination.46 Hence, the βꢀH elimination from the PPh3ꢀligated
complex II-2c requires the lowest barrier among the three Pd(II)
alkoxide complexes. Collectively, the computational study sugꢀ
gests that the reactions with bulky and electronꢀrich alkyl phosꢀ
phine ligands, such as dCypb and PCy3, favor 4a over 4a’ because
these ligands can both promote the βꢀC elimination and inhibit the
βꢀH elimination.
We also computationally investigated the reactivity of the
Pd(dCypb) complex in the oxidative addition of aryl bromide 1a.
In this elementary step, the barrier to the oxidative addition with
the Pd(dCypb) catalyst is 8.6 kcal/mol lower than that with
Pd(PCy3)2 (TS4 vs TS3, see details in Figures S5 and S6). The
high reactivity with the dCypb ligand in the oxidative addition
step is due to the preꢀdistorted geometry of the Pd(0) catalyst with
bidentate phosphine ligands that reduced the catalyst distortion
energy in the transition state. Taken together, these DFT calculaꢀ
tions indicate the dCypb ligand is effective in controlling the
chemoselectivity in the βꢀC elimination step and enabling rapid
oxidative addition of aryl bromides.
The Pd/P ratio also appeared to be important for this transforꢀ
mation. Different loadings of dCypb were tested under the otherꢀ
wise standard conditions (Scheme 2). When 5 mol% of dCypb
ligand was used (Pd/P = 1:1), a complex mixture was formed with
a poor conversion of aryl bromide 1a. The 1:2 and 1:3 Pd/P ratios
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both proved to be efficient giving comparable yields of the deꢀ
sired product. In contrast, a 1:4 Pd/P ratio completely inhibited
the reaction, giving nearly no conversion of both starting materiꢀ
als. We reasoned that excess phosphine ligands would suppress
formation of the coordinatively unsaturated 14ꢀelectron Pd(0)
species (vide supra, Figure 4), which in turn would inhibit the
oxidative addition with aryl bromides.
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Scheme 2. The Ligand Ratio Effect
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NBE Effect: Besides simple NBE, a variety of substituted
NBEs have also been examined under the optimal reaction condiꢀ
tion (Scheme 5). For example, Yu and coworkers demonstrated
that methyl norborneꢀ2ꢀcarboxylate (N2) is particularly effective
in the Pd/NBEꢀcatalyzed meta C−H functionalization reactions.50
In the Catellaniꢀtype annulation between aryl iodides and epoxꢀ
ides, we recently found the N3 was more selective than regular
NBE.51 However, for the reaction with aryl bromide 1a all the
electronꢀdeficient norborneꢀ2ꢀcarboxylates (N2ꢀN4) only gave a
trace amount of the desired product 4a. The endoꢀ5ꢀnorborneꢀ2ꢀ
carboxamide N5, previously used in the ortho acylation,31b gave a
slightly lower yield. The 5ꢀnorborneneꢀ2ꢀcarboxylic acid potassiꢀ
um salt (N6), recently employed by Zhou and coworkers,52 led to
a low yield probably due to its poor solubility in 1,4ꢀdioxane.
Finally, ester substitutions at NBE different positions (N7 and N8)
also showed low activity.
Halide effect: Besides the oxidative addition (Step A, Figure
1A), we found, switching from aryl iodides to aryl bromides, the
steps after C−N bond formation could also be affected. For examꢀ
ple, 2ꢀiodoanisole gave 76% of the desired amination product 4a
with only 9% NBEꢀattached sideꢀproduct 4a’ when using tri(4ꢀ
trifluoromethylphenyl)phosphine as the ligand. However, 2ꢀ
bromoanisole gave 41% 4a and 38% 4a’ under the same reaction
conditions (Scheme 3). Considering the large difference of the
4a/4a’ ratios in these results, we hypothesized that the halide leavꢀ
ing group from the substrate likely influenced the steps after the
reaction of ANP with the amine electrophile. To test this hypotheꢀ
sis, 20 mol% CsI was added to the reaction with aryl bromide
under the otherwise identical conditions. Indeed, the 4a/4a’ ratio
was significantly improved from nearly 1:1 to 3:1.47
Scheme 5. The NBE Substitution Effecta
Scheme 3. The Iodide Effect for Aryl Bromide Substrates
Regarding this halide effect, we tentatively propose that the ioꢀ
dide anion may either promote the βꢀC elimination or inhibit the
βꢀH elimination. It has been known for the reactions with platiꢀ
num complexes [PtX(alkyl)(diphosphine)] (X = Cl, Br, I) that the
one with iodide as the X ligand gives faster βꢀH elimination than
those with bromide and chloride.48 However, a more detailed
mechanistic explanation remains to be disclosed at this stage.49
a Run on a 0.2 mmol scale (0.1 M) for 14 h with 1.6 equiv of 2a
1
Reductant effect: Clearly, besides promoting βꢀC elimination,
slowing down the βꢀH elimination should also help to minimize
formation of undesired product 4a’. Indeed, increasing the steric
of the reductant (secondary alcohols) from isopropanol to the (−)ꢀ
borneol 3 decrease formation of 4a’. More interestingly, using the
corresponding deuterated alcohol, i.e. d8ꢀisopropanol, that should
give a slower βꢀH elimination than the normal isopropanol, the
ratio of 4a/4a’ was also enhanced (Scheme 4). Altogether, the
observed reductant effect is consistent with the hypothesis that
slow βꢀH elimination would inhibit formation of NBEꢀattached
sideꢀproduct 4a’.
and 1.0 equiv of 3; yields were determined by HꢀNMR using
1,3,5ꢀtrimethoxylbenzene as the internal standard.
Since simple NBE (N1) gave the best result, the use of a cataꢀ
lytic amount of NBE was then attempted under the otherwise
standard reaction conditions (Scheme 6). While 1 equiv of NBE
gave the highest efficiency, decreasing the loading to 50 or 25
mol% gave similar or comparable yields. Interestingly, when 10
mol% of NBE was used instead (Pd:NBE =1:1), 60% yield of
product 4a was still obtained, suggesting that NBE indeed beꢀ
haved as a coꢀcatalyst in this transformation. Due to the convenꢀ
ience and low cost of NBE, 1 equiv of NBE was employed subseꢀ
quently to explore the substrate scope.
Scheme 4. The Isotope Effect of the Reductant
Scheme 6. Examination of the NBE Loading a
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chloride (4j), free tertiary benzyl alcohol (4l), nitrile (4m), aldeꢀ
hyde (4n), methyl ester (4o) and epoxide (4p), are tolerated. The
scope can be further expanded to naphthalene and heteroarenes.
Bromoꢀsubstituted pyridine (4r), pyrimidine (4s), quinoline (4t),
benzo[b]furan (4u), benzo[b]thiophene (4v), isoquinoline (4w)
and protected isatin (4x) all delivered the desired ortho amination
products in reasonably good yields, therefore showing promise for
medicinal chemistry applications. Note that for certain substrates
the dCpentpb ligand gave slightly higher yields.
1
2
3
4
5
6
7
8
9
a Run on a 0.4 mmol scale (0.1 M) for 14 h with 1.6 equiv of 2a
and 1.0 equiv of 3; yields were determined by HꢀNMR using
Table 3. O-Benzoyl Hydroxylamine Scope for Ortho Amina-
tiona
1
10
11
12
13
14
15
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21
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25
26
27
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58
59
60
1,3,5ꢀtrimethoxylbenzene as the internal standard.
Table 2. Aryl Bromide Scope for Ortho Aminationa
a Run on a 0.3 mmol scale (0.1 M) for 14 h with 1.6 equiv of 2
and 1.0 equiv of 3. All yields are isolated yields.
We then continued to explore the scope of the amine coupling
partners, and bromopyridine 3r was used as the model substrate
(Table 3). Piperidine, azepane, dimethylamine, azetidine and Bocꢀ
protected piperazineꢀderived amination reagents all provided the
desired products in moderate to good yields (5aꢀ5e). Additional
FG tolerance was observed with alkyl sulfide (5i), tertiary benꢀ
zylic alcohol (5n), TBS and MOMꢀprotected secondary alcohols
(5f and 5h), carbamate (5e) and benzodioxole (5m). The protected
4ꢀpiperidone moiety (5g) could be converted to free aniline
through ketal hydrolysis and retroꢀazaꢀ1,4ꢀaddition.21,53 The comꢀ
plex Oꢀbenzoyl hydroxylamine, derived from commercial drug
paroxetine, was successfully coupled to give an interesting prodꢀ
uct (5m).
a Run on a 0.3 mmol scale (0.1 M) for 14 h with 1.6 equiv of 2a
and 1.0 equiv of 3. All yields are isolated yields. 11 mol%
dCpentapb·2HBF4 was used instead of dCypb.
b
Substrate scope: With the optimized reaction conditions in
hands, the scope of aryl bromides was investigated next (Table 2).
We first tested different FGs at the ortho position of aryl bromides.
Both electronꢀrich (4a, 4d) and ꢀdeficient (4e) substrates smoothly
gave the desired products in good yields. Bulky substituents at the
ortho position, such as isopropyl (4c) and ketal (4g), were toleratꢀ
ed. Ester, ketal and glycoside moieties proved compatible under
the reaction conditions (4fꢀh). The FG tolerance was further exꢀ
amined with different 2ꢀbromoanisole derived substrates (4iꢀp). A
broad range of FGs, including methoxy ether (4k), fluoride (4i),
Besides orthoꢀsubstituted aryl bromides, para and metaꢀ
substituted substrates have also been evaluated (Scheme 7). Simiꢀ
lar to the prior observation when using aryl iodides,29 paraꢀ
substituted aryl bromides afforded the 1,3ꢀdiaminated products. It
is noteworthy that no monoꢀamination product was observed in all
the cases. Metaꢀsubstituted aryl bromides, such as the 1ꢀbromoꢀ3ꢀ
isopropylbenzene and 3ꢀbromobenzotrifluoride 8, did not give
either monoꢀ or diꢀsubstituted products; instead, the NBEꢀattached
compound (9) was formed as the major sideꢀproduct.
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a The reactions were operated using the conditions described in
Scheme 7. Ortho Amination of Aryl Bromides without Or-
Table 2 except replacing alcohol 3 with the corresponding nucleꢀ
ophiles.
1
2
tho Substitution
3
4
5
6
7
8
9
Synthetic applications: The synthetic utility of this method
was then tested. Sequential crossꢀcoupling55 plays an important
role in synthesis of complex aromatic compounds and is often
employed in pharmaceutical research.56 Using commercially
available bromoꢀiodoarene 15, selective coupling at the iodide site
via Sonogashira reaction afforded alkyne 16. Subsequently, ortho
amination occurred smoothly to afford 3,5ꢀdisubstituted anisole
17 (Scheme 9A). Hence, the ArBrꢀbased Pd/NBE catalysis offers
an additional option for preparing metaꢀsubstituted arenes.
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11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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49
50
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54
55
56
57
58
59
60
Scheme 9. Synthetic Utility of ArBr-Based Ortho Amination.
Other ipso functionalization: Besides coupling with hydride
as the nucleophile, other classes of ipso coupling with different
nucleophiles also worked smoothly using largeꢀbiteꢀangle ligands
with flexible backbones (Scheme 8). DPEphos proved to be a
better ligand than dCypb for Chen’s ipso MizorokiꢀHeck ortho
amination reaction.30a Sonogashira quench with masked terminal
acetylides30e afforded the desired alkynylation product. Neopentyl
diolꢀderived boronates were found to be a better coupling partner
to deliver ipso arylation products.30c Finally, Ritter’s ipso borylaꢀ
tion with B2(pin)2 also provided the desired aryl boronic ester
13.21 Due to its instability on column chromatography, compound
13 was further transformed to the corresponding aryl bromide
(14),54 offering an intriguing netꢀortho amination of 1a.
Scheme 8. Different Ipso Functionalization in the Ortho
Amination of Aryl Bromidesa
CO2t-Bu
OMe
CO2t-Bu
63%
DPEphos instead of dCypb
N
O
Encouraged by the success of the sequential crossꢀcoupling, we
envisioned that merging the classical ArIꢀbased Catellani reaction
with the current ArBrꢀbased method would realize a rapid access
to multiꢀand diverseꢀsubstituted aromatic compounds from polyꢀ
haloarenes. Starting with 2ꢀbromoꢀ6ꢀiodoanisole 18, ortho methꢀ
ylation/ipso Heck reaction,30g followed by ortho amination with
either hydride or Sonogashira quench, provided tetraꢀ or pentaꢀ
substituted arenes efficiently (Scheme 9B). It is noteworthy that
for the pentaꢀsubstituted product (21) all the five substituents are
different from each other, containing all three hybridized forms of
carbons (sp to sp3), oxygen and nitrogen groups. To the best of
knowledge, this represents the first example of combining two
different Pd/NBE catalysis reactions into a single arene substrate,
showing promise for efficient generation of a diverse range of
polyꢀsubstituted arenes.
10
Me
HO
Me
OMe
Ph
Ph
O
61%
2a
N
N
O
OBz
11
+
O
O
Me
Me
Me
Me
B
OMe
OMe
Br
70%
N
1a
O
12
Me
Me
Me
O
O
Me
Me
Me
OMe
B
B
Me
Me
Bpin
O
O
62%
NMR yield
N
13
O
Finally, this method is applied in a twoꢀstep metaꢀamination of
heterocycles. One merit of this protocol is the avoidance of using
directing groups.50b,f,57 Bromination of the commercially available
8ꢀmethoxyquinoline with NBS gave exclusively C5ꢀbrominated
product 22 in nearly a quantitative yield (Scheme 10A). Subseꢀ
quent ortho amination afforded C6ꢀaminated quinoline 23 in 98%
yield on a gram scale with 5 mol% Pd. Further lowering the Pd
OMe
CuBr2
net ortho amination
Br
N
47% for
O
two steps
14
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loading to 1 mol% still gave the desired product with 42 turnovers.
On the other hand, amination of pyridine 24 resulted in an insepaꢀ
rable mixture of 4.2: 1 regioꢀisomers; however, directly subjecting
this mixture to the ortho amination conditions provided a single
regioisomer of the C4ꢀamination product 26 in 83% yield
(Scheme 10B). It is worthy to mention that an alternative route to
product 26 could be through the Irꢀcatalyzed C−H borylation of
pyridine 24,58 followed by electrophilic amination59 or
Chan−Evans−Lam coupling.60
1
2
3
4
5
6
7
8
9
Scheme 10. Stepwise Meta-Amination of Heterocycles
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
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34
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45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
a Run on a 0.3 mmol scale (0.1 M) for 14 h with 1.8 equiv of
27a, 1.0 equiv of 3, 1.5 equiv of tꢀbutyl acrylate, 2.0 equiv of
NBE and 3.0 equiv of Cs2CO3; all yields are isolated yields.
2.2 Ortho acylation. In 2015, we reported an initial study on
ortho acylation/ipso hydrogenation using a bifunctional mixed
anhydride.31b Concurrently, the Liang and Gu groups developed
ortho acylation/ipso Heck using symmetrical anhydrides or acyl
chlorides as electrophiles.31a,c In all these cases, only aryl iodides
were used as substrates, and the electronꢀdeficient less bulky triꢀ
furylphosphine was found to give the best results.61 To enable the
use of aryl bromides as substrates, ortho acylation/ipso Heck couꢀ
pling was chosen as the model reaction. Unsurprisingly, applying
the trifurylphosphine conditions directly to aryl bromides led to
very low conversion. To our delight, analogous to the ortho amiꢀ
nation reaction, large biteꢀangle bidentate phosphine ligands with
flexible backbones also worked well for the ortho acylation. A
survey of ligand effects revealed DPEphos to be optimal.
Table 5. Carboxylic Acid Anhydride Scopea
The aryl bromide scope was then explored using anhydride 27a
as the coupling partner (Table 4). A range of substituents and FGs,
such as ketals (28e) and tertiary alcohols (28g), could be tolerated
on the arene substrates. Quinoline (28h) and benzofuranꢀderived
(28i) substrates also participated in this transformation. When 1ꢀ
bromonaphthylene was used, 90% yield of the desired acylation
product (28c) was obtained. The acid anhydride scope is also
reasonably broad (Table 5). Sterically hindered anhydrides, such
as 2ꢀmethyl and 2,6ꢀdimethoxyl benzoic anhydrides (29a), gave
significantly higher yields than the simple benzoic anhydride
(29b). Aryl chloride (29c) is compatible in this reaction. Hetꢀ
eroarenes, such as thiophene (29d), and ferrocenes (29f) were also
tolerated. Besides aromatic acyl groups, the cyclopropylꢀderived
one was also successfully introduced with aryl bromides (29e), in
which epimerization was not observed.
a Run on a 0.3 mmol scale (0.1 M) for 14 h with 1.8 equiv of
27; 1.0 equiv of 3; 1.5 equiv of tꢀbutyl acrylate, 2.0 equiv of NBE
and 3.0 equiv of Cs2CO3; all yields are isolated yields.
Table 4. Aryl Bromide Scope for Ortho Acylation/Ipso Heck
Reactiona
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With preliminary success of the reactions using activated benꢀ
1
2
3
4
5
6
7
8
zyl halides as the electrophile, ortho alkylation with unactivated
alkyl halides,64 which has been utilized in several elegant total
syntheses,65 was investigated next. 2ꢀBromoanisole 1a was again
employed as the model substrate. When alkyl iodides (e.g. BuI)
were employed as the alkylating reagent, regardless the choice of
phosphine ligands, the reaction proceeded with a low conversion
without forming any desired product. It is likely that alkyl iodides
may react with Pd(0) faster than 2ꢀbromoanisole. Hence, a weaker
alkylating reagent, such as alkyl bromides, was tested. To our
delight, when BuBr was used as the electrophile, triꢀnꢀ
butylphosphine was found to give optimal results at this stage
(Scheme 11). In addition, ortho methylation was realized using
methyl 4ꢀnitrobenzenesulfonate as the electrophile, given that
methyl bromide, a toxic gas, is not convenient to handle. Considꢀ
ering the importance of methylation of arenes66 and heteroarenes67
in drug design,68 this method is expected to be useful for mediciꢀ
nal chemistry research. While the efficiency of these ortho alkylaꢀ
tion reactions remains to be further improved, they nevertheless
show the feasibility of employing widely available aryl bromides
as suitable substrates.
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21
22
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56
57
58
59
60
Figure 4. Xꢀray Crystal structure of compound 29f.
2.3 Ortho alkylation. Ortho alkylation with alkyl halides has
been the first Catellani reaction reported.7a However, the use of
aryl bromides for ortho alkylation remained to be developed. The
feasibility of aryl bromideꢀmediated ortho alkylation was first
explored with benzyl electrophiles, in which the corresponding
reactions with aryl iodides were reported by Lautens and
Liang.20,62 When benzyl bromides were employed as the electroꢀ
phile, no desired benzylation product was observed, which is likeꢀ
ly due to the strong oxidative ability of benzyl bromides comꢀ
pared to aryl bromides. However, combining benzyl chlorides as
the electrophile and tris(4ꢀmethoxyphenyl)phosphine as the ligꢀ
and,63 the desired benzylation product 31a was isolated in 64%
yield with 2ꢀbromoanisole as the substrate (Table 6). In addition,
both electronꢀrich and ꢀdeficient benzyl chlorides gave the desired
products in comparable yields (31b and 31c). Moreover, bromoꢀ
heteroarenes, such as quinoline 31g and pyrimidine 31h, are also
competent substrates.
Scheme 11. Ortho Alkylation of Aryl Bromides with Unacti-
vated Alkyl Electrophiles
CO2Me
OMe
nBuBr
Me
10 mol% Pd(OAc)2
Bu) P•HBF
NBE, Cs2CO3
acrylates
59%
OMe
20 mol% (n-
32
3
4
Br
1,4-dioxane, 100°C
CO2t-Bu
MeONs
47%
OMe
1a
Me
33
CONCLUSIONS
In summary, we describe the efforts of developing general apꢀ
proaches for arylꢀbromideꢀmediated Pd/NBE catalysis, in which
ortho amination, acylation and alkylation have been realized using
Oꢀbenzoyl hydroxylamines, carboxylic acid anhydrides and alkyl
halides respectively as electrophiles. For the ortho amination and
acylation of aryl bromides, electronꢀrich bidentate phosphines
with large bite angles and flexible backbones generally worked
efficiently. For ortho benzylation and alkylation, monoꢀdentate
tris(4ꢀmethoxyphenyl)phosphine and tributylphosphine were
found to be superior than bidentate ligands. The conditions (at
least for ortho amination) are also general for introducing various
substituents, such as vinyl, alkynyl, boryl groups or hydrogen, at
ipso positions. The high chemoselectivity and tolerance of various
heterocycles observed in this study should make these methods
attractive for medicinal chemistry research. Allowing aryl broꢀ
mides for Pd/NBE catalysis also permits development of sequenꢀ
tial functionalization strategies for constructing more complex and
diverse aromatic compounds, therefore offering new strategic
insights for bond disconnection approaches. The knowledge obꢀ
tained from the DFT study should shed light on the choice of
ligands for Pd/NBE catalysis. Further improvement of the catalyst
efficiency and efforts towards expanding the substrate scope to
more challenging aryl chlorides are ongoing.
Table 6. Ortho Alkylation/Ipso Heck Reaction of Aryl Bro-
mides with Benzyl Chloridesa
10 mol% Pd(OAc)2
20 mol% P(C6H4-OMe)3
NBE, Cs2CO3
CO2t-Bu
R
Cl
R1
OMe
Br
t-butyl acrylate
+
1,4-dioxane, 95°C
R2
30
31
CO2t-Bu
CO2t-Bu
CO2t-Bu
OMe
OMe
OMe
CO2Me
OMe
31a 64%
31b
63%
31c 54%
OAc
CO2t-Bu
OMe
CO2t-Bu
CO2t-Bu
Et
OMe
OMe
31d 71%
31e
31f 67%
81%
AcO
AcO
AcO
AcO
O
CO2t-Bu
OMe
MeO
CO2t-Bu
CO2t-Bu
O
OMe
N
OMe
OMe
N
MeO
N
31i 63%
Experimental Section
31g 66%
31h 57%
General procedure of palladium/norbornene-catalyzed ortho
amination of aryl bromides. An ovenꢀdried 4 mL vial was
charged with aryl bromide (0.3 mmol, 1.0 equiv), Oꢀbenzoyl hyꢀ
droxylamine (0.3 mmol, 1.6 equiv), (−)ꢀborneol (46.2 mg, 0.3
a Run on a 0.3 mmol scale (0.1 M) for 14 h with 2.0 equiv of
30; 1.0 equiv of 3; 1.5 equiv of tꢀbutyl acrylate, 2.0 equiv of NBE
and 3.0 equiv of Cs2CO3; All yields are isolated yields.
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mmol, 1.0 equiv), norbornene (28.2 mg, 0.3 mmol, 1.0 equiv),
rial is available free of charge via the Internet at
palladium acetate (6.7 mg, 0.03 mmol, 0.1 equiv) and a magnetic
stir bar. The vial was sealed in the air and transferred in a nitroꢀ
genꢀfilled glovebox. 1,4ꢀBis(dicycloꢀhexylphosphino)butane (14.9
mg, 0.033 mmol, 0.11 equiv) and cesium carbonate ( 245 mg, 0.75
mmol, 2.5 equiv) were added to the vial in the glove box. 1,4ꢀ
Dioxane (3 ml) was added, and the vial was then sealed with
PTFE lined cap in the glovebox. The resulting mixture was stirred
at room temperature for 10 minutes until the all the palladium
acetate was fully dissolved. The vial was subsequently transferred
out of glovebox and stirred on a pieꢀblock preheated to 90oC for
14 hours. After completion of the reaction, the mixture was filꢀ
tered through a thin pad of celite. The filter cake was washed with
ethyl acetate, and the combined filtrate was concentrated. The
residue was directly purified by flash column chromatography on
silica gel to yield the desired product.
http://pubs.acs.org.
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8
AUTHOR INFORMATION
Corresponding Author
*pengliu@pitt.edu
*gbdong@uchicago.edu
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENT
University of Chicago, Eli Lilly, University of Pittsburgh, NIGMS
(1R01GM124414ꢀ01A1) and the National Science Foundation
(CHEꢀ1654122) (P.L.) are acknowledged for research support.
We thank Dr. Zhou Xuan, Dr. Hee Nam Lim and Dr. Ziqiang
Rong for donation of several aryl bromides. Mr. KiꢀYoung Yoon
is acknowledged for Xꢀray crystallography. Calculations were
performed at the Center for Research Computing at the University
of Pittsburgh and the Exꢀtreme Science and Engineering Discovꢀ
ery Environment (XSEDE) supported by the NSF.
General procedure of palladium/norbornene-catalyzed ortho
acylation of aryl bromides. An ovenꢀdried 4 mL vial was
charged with aryl bromide (0.3 mmol, 1.0 equiv), carboxylic acid
anhydride (0.54 mmol, 1.8 equiv), tertꢀbutyl acrylate (56.7 mg,
0.45 mmol, 1.5 equiv), norbornene (56.4 mg, 0.6 mmol, 2.0
equiv), dichlorobis(acetonitrile)palladium(II) (7.8 mg, 0.03 mmol,
0.10 equiv), bis[2ꢀ(diphenylphosphino)phenyl] ether ( 16.1 mg,
0.03 mmol, 0.10 equiv) and a magnetic stir bar. The vial was
sealed in the air and transferred in a nitrogenꢀfilled glovebox.
Cesium carbonate (294.0 mg, 0.9 mmol, 3.0 equiv) was added to
the vial in the glove box. 1,4ꢀDioxane (3 ml) was added, and the
vial was then sealed with PTFE lined cap in the glovebox. The
resulting mixture was stirred at room temperature for 15 minutes
until the all the dichlorobis(acetonitrile)palladium(II) was fully
dissolved. The vial was subsequently transferred out of glovebox
and stirred on a pieꢀblock preheated to 100oC for 14 hours. After
completion of the reaction, the mixture was filtered through a thin
pad of celite. The filter cake was washed with ethyl acetate, and
the combined filtrate was concentrated. The residue was directly
purified by flash column chromatography on silica gel to yield the
desired product.
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′ꢀDisubstituted Vinylarenes." Angew. Chem. Int. Ed. 1997, 36, 119ꢀ122;
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General procedure of palladium/norbornene-catalyzed or-
tho benzylation of aryl bromides. An ovenꢀdried 4 mL vial was
charged with aryl bromide (0.30 mmol, 1.0 equiv), benzyl chloꢀ
ride (0.60 mmol, 2.0 equiv), tertꢀbutyl acrylate (56.7 mg, 0.45
mmol, 1.5 equiv), norbornene (56.4 mg, 0.6 mmol, 2.0 equiv, 2.0
equiv) and a magnetic stir bar (“substrate vial”). Palladium acetate
(6.7 mg, 0.03 mmol, 0.1 equiv) and tris(4ꢀmethoxyphenyl)ꢀ
phosphine (21.1 mg, 0.06 mmol, 0.2 equiv) were put in another
ovenꢀdried 4 mL vial (“Pd/ligand vial”). Both vials were transꢀ
ferred in a nitrogenꢀfilled glovebox. 1,4ꢀDioxane (1 ml) was addꢀ
ed to the Pd/ligand vial. The resulting mixture was stirred at room
temperature for 10 minutes until the all the palladium acetate was
fully dissolved to give a bright yellow homogenous solution. 1,4ꢀ
Dioxane (2 ml) and cesium carbonate (294.0 mg, 0.9 mmol, 3.0
equiv) were added to another vial in the glove box. The palladiꢀ
um/ligand solution was transferred to the substrate vial that was
then sealed inside the glovebox. The vial was subsequently transꢀ
ferred out of glovebox and stirred on a pieꢀblock preheated to
95oC for 14 hours. After completion of the reaction, the mixture
was filtered through a thin pad of celite. The filter cake was
washed with ethyl acetate, and the combined filtrate was concenꢀ
trated. The residue was directly purified by flash column chromaꢀ
tography on silica gel to yield the desired product.
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ASSOCIATED CONTENT
(9) Catellani, M.; Motti, E.; Minari, M. "Symmetrical and Unsymmetrical
2,6ꢀdialkylꢀ1,1'ꢀbiaryls by Combined Catalysis of Aromatic Alkylation via
Text, figures, tables, and CIF files giving experimental proceꢀ
dures, kinetics data, and crystallographic information. This mateꢀ
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Journal of the American Chemical Society
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