Additive-Free Palladium-Catalyzed Decarboxylative Cross-Coupling of Aryl Chlorides

Article abstract of DOI:10.1021/acs.orglett.9b01620

The cross-coupling of sodium (hetero)aryl carboxylates with (hetero)aryl chlorides proceeds with 1 mol % palladium catalyst and does not require inorganic base, silver salts, or copper salts. This coupling uses two low energy partners, and the only stoichiometric byproducts are carbon dioxide and sodium chloride. The substrate scope includes less activated aryl chlorides and carboxylates (>25 examples). The palladium loading could be reduced to 0.1 mol %, and Buchwald-style precatalysts could be used.

Full text of DOI:10.1021/acs.orglett.9b01620

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Additive-Free Palladium-Catalyzed Decarboxylative Cross-Coupling
of Aryl Chlorides
Ryan A. Daley, En-Chih Liu, and Joseph J. Topczewski*
Department of Chemistry, University of Minnesota Twin Cities, Minneapolis, Minnesota 55455, United States
S
* Supporting Information
ABSTRACT: The cross-coupling of sodium (hetero)aryl
carboxylates with (hetero)aryl chlorides proceeds with 1 mol
% palladium catalyst and does not require inorganic base, silver
salts, or copper salts. This coupling uses two low energy partners,
and the only stoichiometric byproducts are carbon dioxide and
sodium chloride. The substrate scope includes less activated aryl
chlorides and carboxylates (>25 examples). The palladium
loading could be reduced to 0.1 mol %, and Buchwald-style precatalysts could be used.
ross-coupling is a widely used reaction manifold that
enables the rapid construction of (hetero)biaryl bonds.1,2
Scheme 1. Decarboxylative Coupling with Aryl Chlorides
C
However, the nucleophilic coupling partner (boronic acid or
other arylmetal species) can be unstable, difficult to access,
and/or expensive.3−6 Decarboxylative cross-coupling uses
benzoic acids or benzoate salts as potential replacements for
more expensive and less stable nucleophilic cross-coupling
partners.7−16 Benzoic acids are readily available, stable, low
cost, and low energy starting materials. However, decarbox-
ylative cross-coupling reactions have been limited by (i) the
use of multiple metals, (ii) mechanistic ambiguity, (iii) high
reaction temperatures, and (iv) limited substrate scope.9,17
Additionally, aryl bromides, iodides, and triflates are the most
common electrophiles in decarboxylative cross-couplings
because of their increased reactivity toward oxidative
addition.18−20 However, these electrophiles are less accessible
and generate more toxic byproducts than aryl chlorides.18,21
The reaction of aryl chlorides with benzoate salts represents
the coupling of two of the most stable, lowest energy, and most
readily available coupling partners. As such, developing new
cross-coupling reactions between benzoate salts and aryl
chlorides is desirable.
In 2008, Gooβen reported the first decarboxylative cross-
coupling with aryl chlorides.22 This system used both copper
and palladium co-catalysts (Scheme 1a). In 2010, Liu23 and
Forgione24,25 published separate reports on the palladium-
catalyzed coupling of benzoate salts or heteroaryl carboxylic
acids, respectively. These reactions proceeded with aryl
chlorides, bromides, and triflates (Scheme 1b,c).23,24 Both
reactions were limited in scope. The conditions reported by
Liu were only shown to be compatible with polyfluoroben-
zoates, while the conditions reported by Forgione were only
shown to be compatible with 5-membered heteroaromatic
carboxylic acids. Additionally, the later conditions used a
cesium base and a full equivalent of tetrabutylammonium
chloride additive.
judicious choice of (COD)Pd(CH2TMS)2 (Pd1) as the
palladium precatalyst.26,27 Other precatalysts were significantly
less effective. During that work, low yields were observed for
substrates containing an aryl bromide or chloride, which was
likely due to competitive oxidative addition into the carbon−
halide bond. This observation prompted a re-exploration of the
decarboxylative cross-coupling of aryl chlorides. Herein,
improved conditions are disclosed that provide efficient access
to (hetero)biaryl products. Compared with previous reports,
the work described here (i) operates at a lower catalyst
loading, (ii) uses the sodium carboxylate, (iii) is additive free,
and (iv) is compatible with electron-deficient benzoates,
Recently, we reported an intermolecular salt-free double-
Received: May 7, 2019
decarboxylative aryl allylation.26 This reaction was enabled by
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01620
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
electron-rich benzoates, and heteroaryl carboxylates (Scheme
1d).
We began by reinvestigating a substrate that was problematic
for Liu (Scheme 1c).23 A 14% yield was reported for the
decarboxylative cross-coupling of potassium 2,4,6-trifluoroben-
zoate. As reported, in our hands this coupling resulted in less
than 20% of the desired biaryl product (Table 1, entry 1).
Reducing the excess of reagent (entry 14) and changing the
aryl chloride to be the limiting reagent (entry 15) improved
the yield. An unused vial and stir bar were used to avoid
possible contamination from other metals,29 which did not
alter the results (entry 16). Lastly, the scale of the reaction
could be increased 10-fold without an impact on yield (entry
17).
Changing the aryl chloride from electron-deficient substrate
2a to electron-rich substrate 2b substantially decreased the
yield (Table 2, entry 1). A dependence on the electrophile was
Table 1. Optimization of Decarboxylative Cross-Coupling
Table 2. Ligand Optimization with PMPCl
a
b
entry
[Pd]
1a:2a (equiv)
M
X (mol %) yield of 3a (%)
c
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(OAc)2
Pd1
Pd1
Pd1
Pd(OAc)2
Pd2dba3
Pd2
Pd3
Pd4
Pd1
Pd1
Pd1
Pd1
Pd1
Pd1
Pd1
1.5:1.0
1.0:3.0
1.0:3.0
1.0:3.0
1.0:3.0
1.0:3.0
1.0:3.0
1.0:3.0
1.0:3.0
1.0:3.0
1.0:3.0
1.0:3.0
1.0:3.0
1.0:1.5
1.5:1.0
1.5:1.0
1.5:1.0
K
K
K
Li
4
10
10
10
10
10
5
5
5
10
5
1
18
8
42
nd
65
29
trace
56
56
62
69
73
n.d.
74
81
80
84
a
b
entry
ligand
PCy3
PCy3
BrettPhos
BrettPhos
AdBrettPhos
RuPhos
SPhos
temp (°C)
yield 3b (%)
1
2
3
120
140
140
140
140
140
140
140
trace
15
12
34
26
26
85
87
c
Na
Na
Na
Na
Na
Na
Na
Na
Na
Na
Na
Na
Na
4
5
6
7
8
9
10
11
12
13
14
15
XPhos
a
Reaction conditions: benzoate 1a (50 μmol), aryl chloride 2b (75
b
μmol), Pd1 (0.50 μmol), ligand (1.0 μmol), dioxane (0.10 M). Yield
determined by calibrated GC−FID analysis using biphenyl as an
internal standard. Reactions were run in duplicate, and the average
0
1
1
1
c
yield is reported. The reaction was conducted with 1 mol % ligand.
d
16
17
e
1
unexpected because decarboxylation was calculated to be the
rate-determining step in similar reactions,23,30−33 although a
DFT study by Fang34 showed that the rate-determining step
can be highly substrate dependent. These DFT calculations
used PMe3 as a model ligand.23,34 Therefore, these results may
not transfer to catalytic reactions using PCy3 or another ligand.
Furthermore, the room-temperature cross-coupling of aryl
chlorides is known,35−37 and the calculated barrier for
oxidative addition23,38 indicates that this elementary step
should be facile at elevated temperatures. These thoughts
prompted a second cycle of optimization. Increasing the
temperature from 120 to 140 °C afforded a modest
improvement in the yield (entry 2). Use of Buchwald-style
ligands, which are competent at difficult oxidative additions,
provided higher yields (entries 3−8).35,39 In particular, both
SPhos (entry 7) and XPhos (entry 8) were optimal.
Using XPhos, the aryl chloride scope was broad. The two
model compounds were isolated in the expected yields
(Scheme 2, 3a,b). When the scale was increased to 1 mmol,
the yield was not affected (3b). Electronically neutral
electrophiles gave a high yield of the biaryl product (3c−e).
Electrophiles with an electron-withdrawing group in the para
position were competent coupling partners (3f−h). A substrate
with an ortho-electron-donating group (3i) or an ortho-
electron-withdrawing group (3j) provided a good yield.
Reactive functional groups such as an ester (3k) or an
aldehyde (3l) were tolerated. Heterocycles were competent
coupling partners for the decarboxylation (3m,n), and a
double-decarboxylative coupling was possible (3o).
a
Reaction conditions: benzoate 1a (50−75 μmol), aryl chloride 2a
(50−150 μmol), [Pd] (0.50−5.0 μmol), PCy3 (1.0−10 μmol),
b
dioxane (0.25 M). Yield determined by calibrated GC−FID analysis
using biphenyl as an internal standard. Reactions were run in
duplicate or triplicate, and the average yield is reported. Reaction was
conducted at 3 times the scale and at 160 °C. Reaction was
conducted using a new, unused stir bar and vial. Reaction was
conducted at 10 times the scale. nd = not detected.
c
d
e
When the temperature was reduced to 120 °C, less than 10%
of the product was obtained even with increased catalyst
loading (entry 2). Changing the precatalyst to Pd1
dramatically improved the yield (entry 3), confirming the
core hypothesis that precatalyst Pd1 is adventitious for this
coupling. Using a sodium benzoate instead of a potassium
benzoate improved the yield, while the lithium benzoate was
unreactive (Table 1, entries 4 and 5). The use of the sodium
benzoate with Pd(OAc)2 was beneficial; but it was still inferior
to the reaction with precatalyst Pd1 (entry 5 vs 6). The
common precatalyst Pd2dba3 was unreactive, which may be
due to nanoparticle formation (entry 7).28 Other precatalysts,
which are designed to liberate Pd0, were comparable to Pd1
(entries 8−10). Reducing the catalyst loading from 10 mol %
to 1 mol % did not significantly affect the yield (entries 11−
12). No reaction occurred without palladium (entry 13).
A screen of additives was conducted to test the robustness of
the reaction (see the Supporting Information).40,41 Reactive
B
DOI: 10.1021/acs.orglett.9b01620
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Substrate Scope of Aryl Chlorides
Scheme 3. Substrate Scope of (Hetero)aryl Carboxylates
a
Reactions run in duplicate, and the average isolated yield is reported.
b
c
Reaction time was 48 h at 0.12 M dioxane. Reaction conducted at
d
e
120 °C for 48 h. Reactions conducted at 160 °C for 72 h. Reaction
conducted at 180 °C for 72 h at 0.1 M dioxane. Reactions conducted
at 180 °C for 72 h. Reactions conducted at 180 °C. Isolated as an
inseparable mixture along with an N-arylation byproduct.
f
g
h
a
Reactions were run in duplicate or triplicate, and the average isolated
b
yield is reported. Reaction was conducted with PCy3 at 120 °C.
c
d
and heteroaryl boronic acids are prone to protodeborylation
under Suzuki−Miyaura conditions.4−6
Reaction was conducted on a 1 mmol scale. Reaction time was 48 h.
Reaction was conducted at 160 °C. Reaction was conducted with 0.3
e
f
mmol 2o, with 3 equiv of benzoate using 2 mol % of Pd1, at 160 °C.
Ideally, cross-coupling would be promoted with only a trace
loading of palladium.42 The catalyst loading was stressed to
determine the lowest operable loading (Table 3). A high yield
and conversion were observed using 0.5 mol % of Pd1 (entry
1). Using a 0.1 mol % or 0.05 mol % catalyst loading decreased
the yield due to incomplete conversion (entries 2 and 3). This
demonstrates that up to 800 turnovers are possible with this
system.
Precatalyst Pd1 is not ideal for general use due to its
relatively high cost and sensitivity. Fortunately, the Buchwald
lab recently described air-stable and commercially available
precatalysts with XPhos or SPhos ligands.43,44 These
precatalysts performed on par with precatalyst Pd1 in this
system. Using SPhos-G3 or XPhos-G2 at 1 mol % catalyst
loading resulted in complete conversion and a high yield
(entries 4 and 5). Further reducing the loading to 0.1 mol %
afforded similar results to complex Pd1 across a range of
precatalysts (entries 6−9).
groups such as an alkene, nitrile, ketone, alcohol, aniline,
phenol, furan, indole, or acetal did not inhibit the reaction.
Decyne was fully consumed, but its presence had only a
minimal impact on the yield. The presence of 2,4-
dimethoxypyridine inhibited the reaction, but the presence of
3,5-dimethylpyridine did not affect the yield. Additionally, the
yield was not diminished when the free carboxylic acid was
used in conjunction with 1.1 equiv of Na2CO3 (see the
Supporting Information).
The scope of sodium carboxylates that participate in this
decarboxylative coupling was explored. Other 2,6-difluoro-
arenes were tolerated (Scheme 3, 4a−c). Sodium pentafluor-
obenzoate coupled efficiently (4d) as did other polyfluoroar-
enes (4e−g). Substrates with one or both o-fluorine atoms
substituted for a trifluoromethyl (4h) or methoxy group (4i,j)
afforded acceptable yields of the biaryl. Heterocyclic
carboxylates were competent coupling partners (4k−n). The
benzoate scope for decarboxylative cross-coupling has
limitations, but the scope is complementary to the Suzuki−
Miyaura cross-coupling. In particular, polyfluoroboronic acids
In conclusion, we report a palladium-catalyzed cross-
coupling between sodium carboxylates and aryl chlorides.
This coupling uses a low catalyst loading and two of the lowest
energy coupling partners. Therefore, this process represents
one of the most efficient approaches to cross-coupling, with
C
DOI: 10.1021/acs.orglett.9b01620
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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b
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(h)
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yield of 3b
a
entry
[Pd]
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(%)
(%)
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2
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8
9
Pd1, XPhos
Pd1, XPhos
Pd1, XPhos
SPhos Pd G3 1.0
XPhos Pd G2 1.0
SPhos Pd G3 0.1
XPhos Pd G2 0.1
XPhos Pd G3 0.1
XPhos Pd G4 0.1
0.5
0.1
0.05
72
72
72
24
24
120
120
120
120
>99
83
29
>99
>99
40
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61
27
93
80
23
94
95
38
32
61
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a
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only CO2 and NaCl as stoichiometric byproducts. Further
developments will be reported in due course.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01620.
Experimental procedures and data (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jtopczew@umn.edu.
ORCID
(19) Hills, I. D.; Netherton, M. R.; Fu, G. C. Toward an Improved
Understanding of the Unusual Reactivity of Pd0/Trialkylphosphane
Catalysts in Cross-Couplings of Alkyl Electrophiles: Quantifying the
Factors That Determine the Rate of Oxidative Addition. Angew.
Chem., Int. Ed. 2003, 42, 5749−5752.
Joseph J. Topczewski: 0000-0002-9921-5102
Notes
The authors declare no competing financial interest.
(20) Alcazar-Roman, L. M.; Hartwig, J. F. Mechanistic Studies on
Oxidative Addition of Aryl Halides and Triflates to Pd(BINAP)2 and
Structural Characterization of the Product from Aryl Triflate Addition
in the Presence of Amine. Organometallics 2002, 21, 491−502.
(21) Grushin, V. V.; Alper, H. Transformations of Chloroarenes,
Catalyzed by Transition-Metal Complexes. Chem. Rev. 1994, 94,
1047−1062.
(22) Gooßen, L. J.; Zimmermann, B.; Knauber, T. Palladium/
Copper-Catalyzed Decarboxylative Cross-Coupling of Aryl Chlorides
with Potassium Carboxylates. Angew. Chem., Int. Ed. 2008, 47, 7103−
7106.
ACKNOWLEDGMENTS
Financial support was provided by the University of
Minnesota.
■
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DOI: 10.1021/acs.orglett.9b01620
Org. Lett. XXXX, XXX, XXX−XXX