Functional Group Transposition: A Palladium-Catalyzed Metathesis of Ar-X σ-Bonds and Acid Chloride Synthesis

Article abstract of DOI:10.1021/jacs.8b06605

We describe the development of a new method to use palladium catalysis to form functionalized aromatics: via the metathesis of covalent σ-bonds between Ar-X fragments. This transformation demonstrates the dynamic nature of palladium-based oxidative addition/reductive elimination and offers a straightforward approach to incorporate reactive functional groups into aryl halides through exchange reactions. The reaction has been exploited to assemble acid chlorides without the use of high energy halogenating or toxic reagents and, instead, via the metathesis of aryl iodides with other acid chlorides.

Full text of DOI:10.1021/jacs.8b06605

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Functional Group Transposition: A Palladium-Catalyzed Metathesis
of Ar−X σ‑Bonds and Acid Chloride Synthesis
Maximiliano De La Higuera Macias and Bruce A. Arndtsen*
Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, QC H3A 0B8, Canada
S
* Supporting Information
ABSTRACT: We describe the development of a new
method to use palladium catalysis to form functionalized
aromatics: via the metathesis of covalent σ-bonds between
Ar−X fragments. This transformation demonstrates the
dynamic nature of palladium-based oxidative addition/
reductive elimination and offers a straightforward
approach to incorporate reactive functional groups into
aryl halides through exchange reactions. The reaction has
been exploited to assemble acid chlorides without the use
of high energy halogenating or toxic reagents and, instead,
via the metathesis of aryl iodides with other acid chlorides.
alladium-catalyzed coupling reactions are among the most
1−3
Pheavily exploited transformations in synthetic chemistry.
Central to many of these reactions is the oxidative addition of an
organic-halide or pseudohalide substrate to palladium and the
ultimate liberation of the functionalized product by reductive
elimination. Despite the reversible nature of this oxidative
addition/reductive elimination cycle, it has only recently been
established that aryl-halogen bond oxidative addition to
palladium can itself be reversible and used in synthesis. Hartwig
reported in 2001 that the addition of the sterically encumbered
PtBu3 ligand can facilitate the stoichiometric, reversible reductive
elimination of aryl-halogen bonds from palladium (Figure 1a).4,5
More recently, the importance of this chemistry in catalysis has
beendemonstratedbyLautens, Buchwald, Tong, andotherswith
a number of efficient palladium-catalyzed transformations.6−15
We have reported that palladium-based carbon−halogen
reductive elimination can be used in a different direction and
drive the synthesis of high energy electrophiles such as acid
chlorides from aryl halides and carbon monoxide (Figure
1b).16−19 Acid chlorides are broadly employed in synthesis due
in large part to their high reactivity with a diverse range of
nucleophiles, but classically generated with reactive and
Figure 1. Reversible oxidative addition/reductive elimination of C−X
Bonds.
corrosive chlorinating agents (thionyl chloride, PCl3, or oxalyl
chloride). A key step in this catalytic system is the reductive
elimination of the weak and reactive acid chloride bond. The
chamber systems).21−27 Unfortunately, many of these can
require either specialized equipment or involve reagents/
byproducts that are not compatible with the high reactivity of
acid chlorides.
Inlightoftheabilityofpalladiumcatalyststomediateoxidative
addition and reductive elimination reactions, we questioned if
latter is facilitated by a highly sterically encumbered PtBu3 ligand,
which acts in concert with carbon monoxide coordination to
create a strained Pd(II) intermediate for equilibrium acid
chloride formation.20
One limitation to this catalytic approach to acid chlorides is its
reliance upon carbon monoxide as a reagent, which is toxic and
requiresspecialhandlingasagas. Anumberofalternativesources
ofcarbon monoxide havebeen describedfor use incarbonylation
reactions (e.g., metal carbonyls, CO2, or Skrydstrup’s dual
Received: June 22, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.8b06605
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Journal of the American Chemical Society
Communication
they might offer a fundamentally different way to generate
functionalizedaromatics:viathemetathesisofAr−Xσ-bonds. As
notedabove, arylhalideoxidativeaddition/reductiveelimination
can be reversible with the use of sterically encumbered ligands.6,7
Similarly, the reductive elimination of acid chlorides from
palladium has been found to be a dynamic, equilibrium process
with PtBu3 as ligand, while carbon monoxide insertion is also
reversible with palladium catalysis and exploited in decarbon-
ylative coupling reactions, as well as a route to generate
CO.26,28,29 Together, these suggest the potential to exploit
reversible oxidative addition/reductive elimination reactions to
perform the overall metathesis of Ar−X σ-bonds and thereby
form acid chlorides from simply other acid chlorides. In this
regard, Morandihasrecentlydescribedtheuseofshuttlecatalysis
for the efficient transfer of acid chlorides (or nitriles) between
alkenes and alkynes via dehydrochlorocarbonylation (Figure
1c).30−33 As an alternative, we report here what is to our
knowledge the first example of how palladium-catalyzed
reversible oxidative addition/reductive elimination chemistry
can itself allow the dynamic exchange of different σ-bonded
functional groups between two Ar−X substrates (Figure 1d).
The transformation demonstrates the dynamic nature of
palladium oxidative addition/reductive elimination chemistry,
as well as interpalladium exchange, and offers a method to
synthesize a diverse array of (hetero)aryl acid chlorides in high
yield, with no corrosive byproducts or intermediates and without
the use of carbon monoxide itself as a reagent.
Scheme 1. Catalyst Development for Aryl−X Exchange
Thedevelopmentofthecatalyticexchangeofacidchlorideand
aryl iodide functional groups presents several reaction design
challenges. First, the oxidative addition/reductive elimination
chemistry of two different functionalities, aryl iodide and acid
chloride, must be sufficiently competitive to allow exchange,
despite the established high reactivity of acid chlorides toward
palladium (Figure 1e). The exchange of halides and carbon
monoxide between palladium catalysts must also occur and do so
faster than reductive elimination. Finally, unproductive, yet
precedentedsteps such as aryl chloride reductive elimination and
carbon monoxidedisplacement must not occur, as these could be
irreversible and block the reaction.
Wefirstexaminedtheexchangeofaryliodideand acidchloride
with the Pd(PtBu3)2 catalyst previously employed in catalytic
acid chloride synthesis. No exchange is observed at ambient
temperature, and instead, acid chloride simply undergoes
stoichiometric oxidative addition to palladium (Table S1). The
latter is consistent with previous reports of the rapid and favored
addition of acid chloride to Pd(0). Heating the catalytic reaction
to110°Cresults inthe formation ofanewacidchloride 1bin low
yield (20%, Scheme 1a). Unfortunately, this exchange is
incomplete, and there is catalyst degradation at temperatures
above 110 °C as well as the unproductive aryl chloride reductive
elimination.34
products with Xantphos, and most of the other products are the
starting acid chloride (1a, 60%), aryl iodide (2b, 55%), and the
aryl iodide byproduct (2a, 31%). Decreasing the catalyst loading
leads to analogous results (Table S2).
The exchange of functional groups between the p-methox-
yphenyl and p-tolyl units is a pseudoderivative metathesis
reaction. Performing the reaction in reverse with acid chloride 1b
and aryl iodide 2a leads to the generation of the near identical
mixture of products. The Pd/Xantphos catalyst can therefore
fully scramble Ar−X functional groups to form an equilibrium
mixture of products. Variation of the concentration of reagents
allows the determination of the equilibrium constant for
exchange (Keq = 0.33 0.07, Scheme 1b). The latter is consistent
with the expected ability of the p-methoxy substituent in 1a to
stabilize the acid chloride functionality.
We postulated that the slow exchange of acid chloride/iodide
functionalitiesislikelyrelatedtoinhibitedacidchloridereductive
elimination. While PtBu3 can facilitate ambient temperature
reductive elimination of acid chlorides during carbonylations,
this requires CO coordination to lower the barrier to
elimination.24 We therefore probed if other ligands may be
better suited to favor reductive elimination in the absence of CO.
Although many mono- and bidentate ligands lead to minimal
exchange, we were pleased to find that the large bite angle
Xantphos ligand leads to a significant increase in yield and forms
1b in 35% yield under more mild conditions (80 °C, Scheme 1a).
Importantly, there is minimal generation of decarbonylated
Much as with olefin metathesis or other exchange reactions,
this palladium-catalyzed equilibrium exchange of Ar−X func-
tional groups can, in principle, be directed toward product
formation by modification of the reaction parameters, such asthe
steric/electronic properties in the reagents. One approach to
favor exchange is with ortho-substituted acid chlorides, which
leads to the favored formation of p-methoxybenzoyl chloride
(e.g., 3a,b, Scheme 2 and Table S3). This reaction is presumably
driven by the slow oxidative addition of the sterically
encumbered aryl iodide byproduct to palladium. Even more
dramatic influences can be attained by electronic effects, where
strong electron withdrawing units such as p-COCl (3e) and p-
B
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a
Scheme 2. Influence of Acid Chloride on Equilibrium
Scheme 3. Mechanism Studies on Ar−X Exchange (Ar1 = 4-
C6H4Me; Ar2 = 4-C6H4OMe)
a
p-MeOC6H4l (9 mg, 38 μmol), ArCOCl (38 μmol), Pd2dba3·CHCl3
(2 mg, 1.9 μmol), Xantphos (2 mg, 3.8 μmol), 0.75 mL C6D6, 110 °C,
b
c
20 h, NMR yield. 56 μmol of acid chloride. 56 μmol of aryl iodide.
NO2 (3f) on the acid chloride can drive the exchange to form 1a
in high yield. These transformations can be made nearly
quantitative with a slight excess of either the aryl iodide or acid
chloride. These latter acid chlorides are attractive as reagents: p-
nitrobenzoyl chloride is a commonly employed chromophoric
labeling reagent,35 while terephthaloyl chloride is a high-volume
monomer in polyamide synthesis. They therefore represent
broadly available and inexpensive sources of the acid chloride
functionality to incorporate into products by exchange.
The use of electron deficient acid chlorides offers a broadly
applicable method to convert an array of aryl iodides to acid
chlorides. In order to avoid challenges with catalyst initiation, the
air stable (Xantphos)Pd(4-C6H4NO2)(I) 4a was employed as
catalyst, which leads to clean exchange at 100 °C within 10 h
(Table S4).36−39 As shown in Table 1, the use of p-nitrobenzoyl
chloride with an excess of aryl iodide allows the conversion of a
range of electron neutral or electron rich aryl iodides to acid
chlorides 1a−c,l in good yield (Method I). In each of these, we
observe the formation of aryl iodide as the main byproduct. This
transformation can also allow the transfer acid chloride to
electron deficient aryl iodides (1d−k). The latter are presumably
driven by the strong electron withdrawing nature of the p-nitro
unit in 3f. The reaction shows good functional group
compatibility and can be performed with various halide,
aldehyde, ether, ester, or nitrile aromatics. Heteroaryl iodides
are also viable reagents, with examples including indole,
dioxolane, dioxole, and thiophenes (1t−x). However, sterically
encumbered ortho-substituted aryl iodides are less reactive
(1q,r), and vinyl iodides do not participate in the equilibrium
under these conditions. The aryl iodide can also be used as the
limiting reagent in concert with terephthaloyl chloride (Method
2). Of note, this leads to improved yields in cases where the aryl
iodide contains a potentially coordinating functionality (e.g.,
1o−p,w−x). Coupling this transformation to subsequently react
with nucleophiles can provide a platform to generate a diverse
range of acylated products from aryl iodides via exchange (Table
S5).
proceeds. Xantphos/Pd-aryl and -aroyl complexes 4 can be
generated via oxidative addition reactions (see SI for details).
The combination of palladium-chloride and -iodide complexes
4band4cresultsinthenearimmediateequilibrationofthehalide
ligands between palladium centers to form a time average of
1
products on the H and 31P NMR time scale (Scheme 3a).
Similarly, the reaction of palladium complexes 4h and 4a leads to
the exchange of carbon monoxide within minutes at ambient
temperature to form four separate complexes (Scheme 3b),
demonstrating that CO deinsertion and exchange between
palladiums is also dynamic. While these results suggest the
bimolecular exchange steps in Scheme 1 are viable, a single
palladium cycle involving the oxidative addition of Ar−X to
Pd(II) cannot be ruled out as a possibility. In order to probe the
viability of acid chloride reductive elimination from 4, a second
acid chloride was added to complex 4b, which results in the
exchange of acyl fragments at 50 °C (Scheme 3c). Similarly, the
addition of excess Xantphos to 4b to trap Pd(0) as
(Xantphos)2Pd also generates acid chloride under similar
conditions (Scheme 3d), supporting the viability of a Pd(0/II)
cycle. Preliminary kinetic analysis of the catalytic metathesis
reaction shows a second order rate dependence of palladium
catalyst concentration (Figure S1), which is alsosuggestive ofthe
role of two (Xantphos)Pd fragments in the exchange. There is a
first order rate dependence on aryl iodide concentration, and an
We have performed preliminary mechanistic experiments to
probe how this palladium catalyzed Ar−X σ-bond exchange
C
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Communication
a
Table 1. Palladium-Catalyzed Acid Chloride Synthesis via Metathesis
a
Method I: aryl iodide (0.45 mmol), 4-nitro-benzoyl chloride (56 mg, 0.30 mmol), 4a (14 mg, 15 μmol), 6 mL of C6H6, 90 °C, 20 h, isolated as an
b
amide (see SI). Method II: aryl iodide (38 μmol), terephthaloyl chloride (11 mg, 56 μmol), 4a (1.8 mg, 1.9 μmol), NMR yield. 0.90 mmol of Arl.
c
d
110 °C. In addition to unreacted thiophenyl iodide, we observe 10−15% of PhCOCl and Phl arising from aryl exchange with the ligand (ref 36).
inverse first influence of acid chloride concentration (Figures S2
and S3). Together these imply that elimination of acid chloride
from IV for aryl iodide oxidative addition also contributes to the
rate determining step.
other inexpensive and broadly available acid chlorides. The
approach of using palladium catalysis to achieve exchange of σ-
bonds opens the potential to develop mild methods to form
various functionalized aromatics from stable Ar−X reagents.
Studies directed toward exploiting the latter are currently in
progress.
Overall, while there are several pathways possible for this
reaction, thedataisconsistentwithamechanismsimilartothatin
Figure 1e. In this, the Xantphos/Pd(0) catalyst undergoes
reversible oxidative addition of both aryl iodide and acid chloride
to generate the corresponding palladium-aryl (I) and−acyl
complexes (II). While both are favored steps, acid chloride
oxidative addition appears more rapid, and aryl iodide
concentration can favor the competitive buildup of I, which
can undergo exchange of CO and halide, followed by dynamic
reductive elimination. The large, bidentate Xantphos ligand
presumably lowers the barrier to this reductive elimination by
both steric strain in IV and stabilization of Pd(0),40 and build-up
from this new acid chloride and aryl iodide products.
In conclusion, we have described above what is to our
knowledge the first example of the metathesis of Ar−X σ-bonded
functionalities. This proceeds via the reversible Ar−X oxidative
addition/reductive elimination on palladium with the large bite
angle Xantphos ligand and offers a platform to synthesize acid
chlorides from aryl iodides without carbon monoxide or the use
of caustic reagents or intermediates and, instead, from simply
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.8b06605.
Experimental procedures and compound characterization
(PDF)
AUTHOR INFORMATION
■
Corresponding Author
*bruce.arndtsen@mcgill.ca
ORCID
Bruce A. Arndtsen: 0000-0002-4915-9261
Notes
The authors declare no competing financial interest.
D
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(33) Lian, Z.; Bhawal, B. N.; Yu, P.; Morandi, B. Science 2017, 356,
1059−1063.
(34) 4-Chloroanisole and 4-chlorotoluene are observed in 2% and 5%,
respectively, along with phosphine decomposition. See SI for details.
(35) Tobiszewski, M.; Namiesnik, J.; Pena-Pereira, F. Green Chem.
2017, 19, 5911−5922.
ACKNOWLEDGMENTS
■
We thank NSERC, CONACYT, and the FQRNT supported
Centre for Green Chemistry and Catalysis for funding this
research.
(36) There is imperfect mass balance arising from the aryl exchange of
aromatic units on the Xantphos ligand itself at high temperatures, which
leads to ca. 5−10% phenyl iodide and phenyl acid chloride
formation.37−39
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