Decarboxylative biaryl synthesis from aromatic carboxylates and aryl triflates

Article abstract of DOI:10.1021/ja8050926

A new catalyst system, generated in situ from Cu₂O, 1,10-phenanthroline, PdI₂, and Tol-BINAP, for the first time allows the decarboxylative coupling of carboxylic acids with aryl triflates. In contrast to previous decarboxylative couplings that remained limited to certain activated carboxylates, e.g., ortho-substituted benzoates, this halide-free protocol is generally applicable to aromatic carboxylic acid salts regardless of their substitution pattern. Copyright

Full text of DOI:10.1021/ja8050926

Published on Web 10/25/2008
Decarboxylative Biaryl Synthesis from Aromatic Carboxylates and Aryl
Triflates
Lukas J. Goossen,* Nuria Rodr ´ı guez, and Christophe Linder
FB Chemie - Organische Chemie, TU Kaiserslautern, Erwin-Schroedinger-Strasse, Geb. 54,
6
7663 Kaiserslautern, Germany
Received July 2, 2008; E-mail: goossen@chemie.uni-kl.de
Metal-catalyzed cross-coupling reactions have become estab-
Scheme 1. Mechanism of the Decarboxylative Biaryl Synthesis
lished as universal tools for C-C bond formation, in particular for
1
the synthesis of unsymmetrical biaryls. Typically, stoichiometric
amounts of sensitive and costly organometallic reagents such as
2
3
4
5
6
7
organoboron, -tin, -zinc, -copper, -silicon, or -magnesium
compounds are coupled with organohalides or -pseudohalides under
anaerobic conditions. As an alternative, we have introduced
decarboxylative cross-couplings, in which carboxylic acid salts are
converted into carbon nucleophiles by extrusion of CO
2
and directly
coupled with carbon electrophiles.
The validity of this concept was demonstrated with a biaryl
synthesis from aromatic carboxylates and aryl bromides or chlo-
tion sites at the copper, the reaction is generally applicable to
aromatic carboxylic acid salts regardless of their substitution pattern.
8
rides and an analogous synthesis of aryl ketones from R-oxocar-
The challenge was to identify a ligand environment for the Pd
9
boxylates. This approach combines the key benefit of regiospec-
1
8
that allows the activation of aryl triflates and at the same time
ificity with the broad availability, low cost, and easy handling of
carboxylate substrates. These advantageous properties of carboxylic
acid derivatives have triggered intense investigations of their uses
8
b,16
does not interfere with the Cu-mediated decarboxylation.
We
approached the search for an effective catalyst system using as a
model reaction, the cross-coupling of 4-tolyl triflate (2a) with
potassium 3-nitrobenzoate (1a), that we had been unable to couple
with aryl halides using catalytic amounts of Cu and Pd.
1
0
as substrates in catalysis, and over the past decade, a diverse set
1
1
12
of reaction modes was discovered by Yamamoto, Myers,
1
3
14
15
Forgione, Dixneuf, and us.
A few key experiments selected from our investigation of various
Cu and Pd salts, ligands, and conditions are displayed in Table 1.
We were pleased to find that the replacement of 4-tolyl bromide
with the corresponding triflate directly increased the reaction
turnover from less than one to more than two with our first-
Our decarboxylative biaryl synthesis is mediated by a bimetallic
catalyst: A palladium complex inserts into the C-X bond of the
aryl halide, while the extrusion of CO from the carboxylate takes
2
place within the coordination sphere of a copper-phenanthroline
system, giving rise to an arylcopper species. In a transmetalation
step, a diaryl-Pd species is formed that liberates the biaryl product
via reductive elimination, thus regenerating the original Pd(0)
species and closing the catalytic cycle for palladium. The copper
halide formed alongside has to undergo salt metathesis with the
potassium carboxylate to permit further turnover also of the
decarboxylation catalyst (Scheme 1).
generation system, CuI/1,10-phenanthroline and Pd(acac)
2
(entries
1
, 2), thus confirming the viability of our strategy. The decisive
factor in making the transformation effective was the choice of
phosphine, and we found the sterically demanding, moderately
electron-rich chelating phosphine Tol-BINAP to ideally stabilize
the Pd while maintaining the decarboxylation activity of the Cu at
the highest possible level (entries 3-8). Among the palladium
Mechanistic investigations revealed that the major limitation
observed in the first-generation catalytic decarboxylative biaryl
synthesis, namely its restriction to complexing substrates such as
heterocyclic or ortho-substituted benzoic acids, is due to this
thermodynamically unfavorable exchange of a halide for a nonortho-
sources tested, PdI gave the best results, but other Pd salts may
be used as well (entries 11, 13-15). The Cu cocatalyst is best
2
generated from Cu O and 1,10-phenanthroline, which remained the
2
best commercially available ligand (entries 8-11). The potassium
carboxylate could also be generated in situ, although this gave
slightly inferior yields (entry 19). Other metal cations were less
effective (entry 12). Notably, the reaction was complete within 10
min at 190 °C when conducted in the microwave (entry 18). With
the best catalyst system, the desired 3-nitro-4′-methylbiphenyl (3aa)
was obtained in yields of up to 70% using 15 mol% Cu and 3
mol% Pd catalysts in the polar aprotic solvent NMP when
employing excess triflate (entry 16).
1
6
substituted benzoate derivative at the copper center. A possible
way to make catalytic decarboxylative couplings generally ap-
plicable to aromatic carboxylates regardless of their substitution
pattern would be to find new ligands that increase the preference
of the decarboxylation metal for carboxylate ions. While this is
certainly imaginable for copper-based systems, such an approach
is not likely to allow related Ag/Pd-mediated decarboxylative cross-
coupling reactions to become catalytic in silver due to the stability
This catalyst allows the decarboxylative coupling of 4-tolyl
triflate with various aromatic and heterocyclic carboxylates in
reasonable yields, regardless of their substitution pattern (Table 2).
Notably, even thiophene-3-carboxylate (1i), which had been unre-
8
b,17
of silver halides.
We herein present an alternative solution to
this problem: A new catalyst system was developed that allows
the use of aryl triflates instead of aryl halides in decarboxylative
cross-couplings. As the carboxylates will be able to successfully
compete against the weakly coordinating triflate ions for coordina-
13
active in a mechanistically distinct decarboxylative coupling, was
smoothly converted. The main side reactions observed were
1
5248 9 J. AM. CHEM. SOC. 2008, 130, 15248–15249
10.1021/ja8050926 CCC: $40.75  2008 American Chemical Society

C O M M U N I C A T I O N S
a
a
Table 1. Development of the Catalyst System
Table 3. Scope with Regard to the Triflate Coupling Partner
entry
Cu source
Pd source
phosphine
yield/%
carboxylate
triflate
Ar
product
yield/%
b
1
CuI
”
”
”
”
”
”
”
Pd(acac)2
”
”
”
”
”
”
”
”
”
”
”
Pd(OAc)2
Pd(dba)2
PdI2
”
”
”
”
–
–
11
34
24
39
28
38
36
47
49
14
52
11
49
31
58
70
39
59
52
b
1
”
1
”
”
”
”
”
”
a
o
2b
2c
2b
2d
2e
2f
2g
2h
2i
2-naphthyl-
3-Ac-C6H4-
2-naphthyl-
Ph-
4-MeO-C6H4-
2-Me-C6H4-
4-EtC(O)-C6H4-
4-Cl-C6H4-
quinoline-8-yl-
3ab
3ac
3ob
3od
3oe
3of
3og
3oh
3oi
62
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
b
58
P(Ph)3
P(p-Tol)3
P(Cy)3
BINAP
dppb
Tol-BINAP
”
”
”
”
”
”
”
”
”
”
”
98
91
83
79
45
91
80
CuBr
CuCl2
Cu2O
0
1
2
3
4
5
6
7
8
9
c
b
”
”
”
”
”
”
”
”
7.5 mol% Cu2O, 15 mol% 1,10-phenanthroline, 3 mol% PdI2, 4.5
a
mol% Tol-BINAP, 8.0 mL of NMP, 24 h. Reaction conditions: 1
mmol of potassium carboxylate, 2 mmol of triflate, 5 mol% Cu O, 10
2
mol% 1,10-phenanthroline, 2 mol% PdI2, 6 mol% P(p-Tol)3, 4.0 mL of
NMP, 170°C, 1 h, isolated yields.
d
d,e
f
Overall, by enabling the use of triflates as carbon electrophiles,
a critical limitation of the original decarboxylative biaryl synthesis
has been overcome, namely its restriction to ortho-substituted
benzoates. Ongoing work is directed toward replacing 1,10-
phenanthroline with a customized ligand with the goal of enhancing
the decarboxylation activity of the copper, to allow for milder
reaction conditions and further widen the substrate scope.
f,g
a
Reaction conditions: 1 mmol of potassium 3-nitrobenzoate, 2 mmol
of 4-tolyl triflate, 15 mol% Cu source (7.5 mol% for Cu2O), 15 mol%
,10-phenanthroline, 3 mol% Pd source, 9 mol% phosphine (4.5 mol%
for bidentate), 4 mL of NMP, 170°C, 16 h. Yields determined by GC
using n-tetradecane as internal standard. 1 mmol of 4-bromotoluene
1
b
c
instead of the triflate. Sodium 3-nitrobenzoate instead of potassium
d
e
f
3
°
-nitrobenzoate. 24 h. 1 mmol of 4-tolyl triflate. Microwave, 190
g
Acknowledgment. We thank Saltigo GmbH and NanoKat for
financial support and the Alexander-von-Humboldt-Stiftung for a
fellowship for N.R.
C, 10 min (see Supporting Information). 3-Nitrobenzoic acid instead
of potassium 3-nitrobenzoate, 0.55 mmol of K2CO3, 250 mg of 3 Å
molecular sieves.
a
Table 2. Scope with Regard to the Carboxylate Substrates
Supporting Information Available: Experimental data and proce-
dures for all compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
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Ar
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1
1
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52
58
62
40
53
41
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-tolyl triflate, 7.5 mol% Cu2O, 15 mol% 1,10-phenanthroline, 3 mol%
PdI2, 4.5 mol% Tol-BINAP, 4.0 mL of NMP, 170 °C, 24 h, isolated
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JA8050926
J. AM. CHEM. SOC. 9 VOL. 130, NO. 46, 2008 15249