Palladium/copper-catalyzed decarboxylative cross-coupling of aryl chlorides with potassium carboxylates

Article abstract of DOI:10.1002/anie.200800728

(Chemical Equation Presented) Even non-activated aryl chlorides undergo decarboxylative cross-coupling reactions in the presence of a catalyst system generated in situ from CuI, 1,10-phenanthroline, PdI₂, and di(tert-butyl)biphenylphosphane. The new catalyst is useful for both the synthesis of biaryl compounds from aromatic carboxylates and the synthesis of aryl ketones from salts of α-ketocarboxylic acids (see scheme; FG=functional group; R=aryl, alkyl).

Full text of DOI:10.1002/anie.200800728

Angewandte
Chemie
DOI: 10.1002/anie.200800728
Synthetic Methods
Palladium/Copper-Catalyzed Decarboxylative Cross-Coupling of Aryl
Chlorides with Potassium Carboxylates**
Lukas J. Gooßen,* Bettina Zimmermann, and Thomas Knauber
Over the last few decades, the formation of carbon–carbon
bonds by the transition-metal-catalyzed cross-coupling of
carbon nucleophiles with carbon electrophiles has evolved
into a key synthetic approach for the construction of complex
organic molecules.[1] The main reason for the success of this
reaction type is that it enables the selective connection of
even highly functionalized substrates at positions defined by
two leaving groups of opposite polarity. Numerous cross-
coupling procedures have been developed, for example, the
Suzuki, Negishi, and Kumada reactions. A coupling reaction
is therefore chosen for a given application on the basis of the
availability, stability, and price of the required substrates and
catalyst, as well as the efficiency, selectivity, and convenience
of the reaction protocol.[2]
copper intermediates, which are coupled directly with a
carbon electrophile by a palladium cocatalyst. The proposed
À
mechanism of this catalytic C C bond formation is depicted
in Scheme 1.
In this respect, organic chloride compounds are among the
most attractive carbon electrophiles, particularly on industrial
scale, because they are readily available in great structural
diversity and at low cost.[3] Intensive research has resulted in
the development of effective catalyst systems for the activa-
tion of the carbon–chlorine bond to enable efficient coupling
with various organometallic compounds. Bulky, electron-rich
Scheme 1. Pd/Cu-catalyzed decarboxylative cross-coupling.
With such decarboxylative cross-coupling reactions, it
should be possible to overcome some key limitations of
traditional approaches. Their synthetic potential has been
demonstrated for commercially important biaryl compounds,
for example, valsartan and boscalid.[16,19] However, they have
À
ligands are usually used in these procedures for C Cl bond
activation, for example, phosphanes of the type described by
the research groups of Buchwald,[4] Fu,[5] and Beller,[6]
N-heterocyclic carbenes,[7] phosphites,[6] ferrocenyl phos-
phanes[8] or phosphine oxides,[9] or palladacycles.[10]
À
been developed to a far lesser extent than traditional C C
Although there are significant differences in the func-
tional-group tolerance and reactivity of nucleophilic cross-
coupling partners (e.g. organometallic compounds of the
elements boron,[11] tin,[12] zinc,[13] copper,[14] or magnesium[15]),
their availability and price are often comparable, as they are
accessible by only a limited range of synthetic methods, which
usually involve sensitive organometallic reagents.
bond forming reactions, and improvements in substrate scope
and reaction conditions are vital for them to become
established as true synthetic alternatives. We report herein
an important step in this direction, namely, the development
of a second-generation catalyst that enables the use of non-
activated aryl chlorides for the first time as substrates in
decarboxylative cross-coupling reactions.
In contrast to the above-mentioned cross-coupling reac-
tions of preformed organometallic reagents, Pd/Cu-catalyzed
decarboxylative cross-coupling reactions draw on widely
available, stable, and inexpensive carboxylic acid salts as
sources of the carbon nucleophile.[16,17] The extrusion of CO2
from these substrates takes place within the coordination
sphere of a copper/phenanthroline catalyst[18] to give organo-
To identify an effective catalyst system for the decarbox-
ylative cross-coupling of aryl chlorides, we chose the partic-
ularly demanding cross-coupling of electron-rich and there-
fore poorly reactive 4-chloroanisole with potassium 2-nitro-
benzoate as a model reaction. We tested various combinations
of copper and palladium salts, ligands, solvents, and reaction
conditions (Table 1). As expected, our first-generation cata-
lyst system consisting of copper iodide, 1,10-phenanthroline,
and palladium(II) acetylacetonate, a system that was very
effective in the analogous transformation of aryl bromides,
displayed no activity in this test reaction (Table 1, entry 1).
The addition of bulky, electron-rich phosphanes to
increase the electron-density at the palladium center
appeared to be a promising strategy for creating a more
active catalyst system and thereby facilitating an insertion
into the stable carbon–chlorine bond.[20] However, our
previous experiments with aryl bromides had revealed that
[*] Prof. Dr. L. J. Gooßen, B. Zimmermann, T. Knauber
FB Chemie—Organische Chemie
Technische Universität Kaiserslautern
Erwin-Schrödinger-Strasse Geb. 54
67663 Kaiserslautern (Germany)
Fax: (+49)631-205-3921
E-mail: goossen@chemie.uni-kl.de
Homepage: http://www.chemie.uni-kl.de/goossen
[**] We thank the Deutsche Forschungsgemeinschaft and Saltigo
GmbH for financial support.
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Table 1: Development of the catalyst system.[a]
with regard to the aryl chloride coupling partner. Both
electron-rich and electron-poor aryl chlorides underwent
smooth conversion when common functionalities, such as
ester, ether, cyano, and formyl groups, were present as
substituents on the aromatic ring, with the formation of
compounds 3a–k (Table 2). Moreover, the coupling of 3-
chloropyridine with 1a to give 3l demonstrates that even
basic nitrogen heterocycles are compatible with this trans-
formation.
Entry
Pd source
Phosphane
Yield [%][b]
1
2
3
4
5
6
7
8
9
10
11
12
13
14[c]
15[d]
16
17
18
19
20
21
[Pd(acac)2]
[Pd(acac)2]
[Pd(acac)2]
[Pd(acac)2]
[Pd(acac)2]
[Pd(acac)2]
[Pd(acac)2]
[Pd(acac)2]
[Pd(acac)2]
[Pd(acac)2]
[Pd(acac)2]
[Pd(acac)2]
[Pd(acac)2]
[Pd(acac)2]
[Pd(acac)2]
[Pd(dba)2]
Pd(OAc)2
PdCl2
–
PPh3
binap13
P(iPr)Ph2
PnBu3
PnOct3
PiPr3
PCy3
PCyp3
PtBu3
(o-biphenyl)PCy2
davephos
(o-biphenyl)PtBu2
(o-biphenyl)PtBu2
(o-biphenyl)PtBu2
(o-biphenyl)PtBu2
(o-biphenyl)PtBu2
(o-biphenyl)PtBu2
(o-biphenyl)PtBu2
(o-biphenyl)PtBu2
(o-biphenyl)PtBu2
0
0
5
4
10
39
4
30
21
6
Table 2: Scope of the cross-coupling reaction with regard to the aryl
chloride.[a]
7
Product
Yield [%]
61
Product
Yield [%]
71
60
38
48
17
35
50
53
62
65
[Pd(F6-acac)2]
PdBr2
PdI2
66
88[b,c]
[a] Reaction conditions: CuI (2 mol%), Pd source (2 mol%), ligand
(2 mol%; 1 mol% for bidentate ligands), 1,10-phenanthroline (2 mol%),
NMP (1.5 mL), 1608C, 24 h. [b] Yields were determined by GC analysis
with n-tetradecane as an internal standard. [c] Cu2O (2 mol%) was used
as the copper source. [d] The reaction was carried out in NMP/quinoline
(3:1). acac=acetylacetonate, binap=2,2’-bis(diphenylphosphanyl)-1,1’-
binaphthyl, Cy=cyclohexyl, Cyp=cyclopentyl, davephos=2-dicyclohex-
ylphosphino-2’-(N,N-dimethylamino)biphenyl, dba=trans,trans-dibenzy-
lideneacetone, NMP=1-methyl-2-pyrrolidinone.
71[b,c]
75[b]
55[b,c]
68[b]
66
81
75
many phosphanes, particularly electron-rich phosphanes, also
coordinate to the copper cocatalyst and retard the decarbox-
ylation step. Therefore, the results of varying the phosphane
do not follow a clear trend (Table 1, entries 2–13): Triaryl
phosphanes and linear trialkyl phosphanes were almost
ineffective, a somewhat higher yield was observed with
moderately electron rich, sterically demanding triisopropyl-
phosphane, and tricyclohexylphosphane and extremely bulky
tri-tert-butylphosphane were again less effective. Particularly
high yields were observed with the bulky monodentate ligand
di(tert-butyl)biphenylphosphane, whereas some structurally
related biphenylphosphanes were almost completely ineffec-
tive. We next varied the copper and palladium sources and
found that the presence of halide counterions facilitates the
reaction.[21] A catalyst system generated in situ from CuI and
PdI2 in combination with the ligands 1,10-phenanthroline and
di(tert-butyl)biphenylphosphane was found to be optimal and
mediated the desired transformation in good yields at a low
catalyst loading of 2 mol% each of the copper and palladium
precatalysts.
83[b]
[a] Reaction conditions: CuI (2 mol%), PdI2 (2 mol%), (o-biphe-
nyl)PtBu2 (2 mol%), 1,10-phenanthroline (2 mol%), NMP (1.5 mL),
1608C, 24 h. [b] The reaction was carried out in a mixture of NMP
(1.5 mL) and quinoline (0.5 mL). [c] [Pd(acac)2] (2 mol%) was used as
the Pd source.
The scope of the procedure with regard to the carboxylate
coupling partner was explored with 4-chlorotoluene as the
carbon electrophile. The new catalyst system is effective in the
coupling of all aromatic carboxylic acids that can currently be
decarboxylated with
a
copper/phenanthroline system
(Table 3): Besides potassium 2-nitrobenzoates, other ortho-
substituted aromatic carboxylates, the heterocyclic derivative
2-thiophenecarboxylate, and potassium cinnamate were cou-
pled smoothly with 4-chlorotoluene. The products were
formed in the presence of the palladium (2 mol%) and
copper catalysts (10 mol%) in yields that generally matched
Having identified an efficient reaction protocol that
enables the smooth cross-coupling even of particularly
electron-rich 4-chloroanisole, we next investigated its scope
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Table 3: Synthesis of biaryl compounds and ketones with a range of
sponding biaryl compounds 4n,o in low yields, which never
carboxylic acids.[a]
exceeded the amount of the copper catalyst used.[22]
We were pleased to find that the new catalyst system is
effective without modification in our recently disclosed
decarboxylative synthesis of aryl ketones.[23] In this trans-
formation, acyl nucleophiles are generated from a-oxocar-
boxylates by extrusion of CO2 at a copper catalyst and
coupled directly with aryl halides by a palladium cocatalyst
(Table 3, products 6a–e). The selected examples show that the
aryl bromide substrates used in the original procedure can be
substituted for aryl chlorides with the new catalyst system
without significant decreases in yield.
Product
Yield [%]
80
Product
Yield [%]
76
In summary, we have developed a new catalyst system for
decarboxylative cross-coupling reactions that enables the use
of non-activated aryl chloride substrates for the first time. The
system is generated in situ from CuI, 1,10-phenanthroline,
PdI2, and di(tert-butyl)biphenylphosphane and is generally
applicable to the synthesis of biaryl compounds from the salts
of aromatic carboxylic acids, as well as to the synthesis of aryl
ketones from a-ketocarboxylates. Current studies are
directed towards the development of a new generation of
copper cocatalysts, with which we hope to overcome the
remaining limitations of our decarboxylative coupling reac-
tions, particularly with respect to the range of carboxylic acid
substrates that can be used.
75[b]
90[c]
70
40
65[d]
82[b]
Experimental Section
65
53
General procedure for the synthesis of 3a–l: Compound 1a
(1.50 mmol), copper(I) iodide (0.02 mmol), 1,10-phenanthroline
(0.02 mmol), palladium iodide (0.02 mmol), and di(tert-butyl)biphe-
nylphosphane (0.02 mmol) were placed in an oven-dried 20 mL
crimp-top vial equipped with a septum cap, and the reaction vessel
was evacuated and filled with nitrogen three times. A stock solution of
the aryl chloride 2a–l (1.00 mmol) and the internal GC standard
n-tetradecane (50 mL) in NMP (1.5 mL) was added with a syringe, and
the resulting mixture was stirred at 1608C for 24 h, then poured into
aqueous HCl (1n, 20 mL) and extracted with ethyl acetate (3 ”
20 mL). The combined organic layers were washed with a saturated
solution of sodium hydrogen carbonate and then with brine, dried
over MgSO4, and filtered, and the solvents were removed in vacuo.
Purification of the residue by column chromatography (SiO2, ethyl
acetate/hexane gradient) yielded the corresponding biaryl compound.
For detailed experimental procedures and spectroscopic data, see
the Supporting Information.
82[b]
47[d]
65[b]
13[d]
traces
58[d]
28[d]
73[d]
66[d]
73[d]
Received: February 13, 2008
Revised: April 7, 2008
Published online: August 6, 2008
[a] The part of the molecule that originates from the carboxylate is drawn
on the left-hand side. Reaction conditions: CuBr (10 mol%), PdBr2
Keywords: aryl chlorides · carboxylic acids · cross-coupling ·
decarboxylation · palladium
.
(2 mol%),
(o-biphenyl)PtBu2
(2 mol%),
1,10-phenanthroline
(10 mol%), NMP (1.5 mL), quinoline (0.5 mL), 1708C, 24 h. [b] CuF2
(10 mol%) was used as the copper source. [c] [Pd(acac)2] (2 mol%) was
used as the Pd source. [d] The reaction was carried out by a modified
method (see the Supporting Information).
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