Biaryl synthesis via Pd-catalyzed decarboxylative coupling of aromatic carboxylates with aryl halides

Article abstract of DOI:10.1021/ja068993+

A new strategy for the regiospecific construction of unsymmetrical biaryls is presented, in which easily available salts of carboxylic acids are decarboxylated in situ to give arylmetal species that serve as the nucleophilic component in a catalytic cross-coupling reaction with aryl halides. The catalyst system consists of a copper phenanthroline complex that mediates the extrusion of CO₂ from aromatic carboxylates to generate arylcopper species, and a palladium complex that catalyzes the cross-coupling of these intermediates with aryl halides. This bimetallic system allows the direct coupling of various aryl, heteroaryl, or vinyl carboxylic acids with aryl or heteroaryl iodides, bromides, or chlorides at 160°C in the presence of a mild base such as potassium carbonate. The present scope and potential economic impact of the reaction are demonstrated by the synthesis of 42 biaryls, some of which are of substantial industrial relevance. Remaining challenges and future perspectives of the new transformation are discussed.

Full text of DOI:10.1021/ja068993+

Published on Web 03/22/2007
Biaryl Synthesis via Pd-Catalyzed Decarboxylative Coupling
of Aromatic Carboxylates with Aryl Halides
Lukas J. Goossen,* Nuria Rodr´ıguez, Bettina Melzer, Christophe Linder,
Guojun Deng, and Laura M. Levy
Contribution from the Institut fu¨r Organische Chemie, TU Kaiserslautern,
Erwin-Schro¨dinger-Strasse, Building 54, D-67663 Kaiserslautern, Germany
Received December 15, 2006; E-mail: goossen@chemie.uni-kl.de
Abstract: A new strategy for the regiospecific construction of unsymmetrical biaryls is presented, in which
easily available salts of carboxylic acids are decarboxylated in situ to give arylmetal species that serve as
the nucleophilic component in a catalytic cross-coupling reaction with aryl halides. The catalyst system
consists of a copper phenanthroline complex that mediates the extrusion of CO2 from aromatic carboxylates
to generate arylcopper species, and a palladium complex that catalyzes the cross-coupling of these
intermediates with aryl halides. This bimetallic system allows the direct coupling of various aryl, heteroaryl,
or vinyl carboxylic acids with aryl or heteroaryl iodides, bromides, or chlorides at 160 °C in the presence
of a mild base such as potassium carbonate. The present scope and potential economic impact of the
reaction are demonstrated by the synthesis of 42 biaryls, some of which are of substantial industrial
relevance. Remaining challenges and future perspectives of the new transformation are discussed.
Introduction
The biaryl moiety is an important structural motif in a great
number of biologically active compounds and functional
molecules.1 In Figure 1, the natural product Biphenomycin,2
the pharmaceuticals Valsartan3 and Telmisartan,4 the agrochemi-
cal Boscalid,5 and liquid crystals for LCD screens6 are depicted
as examples of immensely economically valuable biaryls.
Traditional syntheses of biphenyl derivatives7 such as the
Scholl reaction,8 the Gomberg-Bachmann9 reaction, or Ull-
mann-type couplings10 require rather harsh conditions and often
suffer from low yields for the unsymmetrically substituted
(1) (a) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. ReV. 2003, 103,
893-930. (b) Bringmann, G.; Gu¨nther, C.; Ochse, M.; Schupp, O.; Tasler,
Figure 1. Examples illustrating the significance of the biaryl structural
motif.
S. Biaryls in Nature:
A Multi-Facetted Class of Stereochemically,
Biosynthetically, and Pharmacologically Intriguing Secondary Metabolites
In: Progress in the Chemistry of Organic Natural Products; Herz, W.;
Falk, H.; Kirby, G. W.; Moore, R. E., Eds.; Springer-Verlag: New York,
2001; Volume 82. (c) Hajduk, P. J.; Bures, M.; Praestgaard, J.; Fesik, S.
W. J. Med. Chem. 2000, 43, 3443-3447. (d) Bemis, G. W.; Murcko, M.
A. J. Med. Chem. 1996, 39, 2887-2893.
biaryls while recent strategies, including processes that involve
directed ortho-metalation, are limited to a narrow range of
substrates.11 Catalytic cross-coupling reactions, e.g., of orga-
notin,12 -zinc,13 -copper,14 -boron,15 or -magnesium compounds16
constitute the most generally applicable strategy for synthesis
of biaryls (Scheme 1). Among them, the Suzuki-Miyaura
(2) (a) Schmidt, U.; Leitenberger, V.; Griesser, H.; Schmidt, J.; Meyer, R.
Synthesis 1992, 1248-1254. (b) Schmidt, U.; Meyer, R. Leitenberger, V.;
Griesser, H.; Lieberknecht, A. Synthesis 1992, 1025-1030.
(3) (a) Markham, A.; Goa, K. L. Drugs 1997, 54, 299-311. (b) Croom, K. F.;
Keating, G. M. Am. J. CardioVasc. Drugs 2004, 4, 395-404.
(4) (a) Sharpe, M.; Jarvis, B.; Goa, K. L. Drugs 2001, 61, 1501-1529. (b)
Yusuf, S. Am. J. Cardiol. 2002, 89, 18A-26A.
(11) Miura, M.; Nomura, M. Top. Curr. Chem. 2002, 219, 212-237.
(12) (a) Kosugi, M.; Sasazawa, K.; Shimizu, Y.; Migita, T. Chem. Lett. 1977,
301-302. (b) Kosugi, M.; Shimizu, Y.; Migita, T. Chem. Lett. 1977, 1423-
1424. (c) Kosugi, M.; Hagiwara, I; Migita, T. Chem. Lett. 1983, 839-
840. (d) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508-524.
(13) King, O.; Okukado N.; Negishi E. J. Chem. Soc., Chem. Commun. 1977,
683-684.
(14) Lipshutz, B. H.; Siegmann, K.; Garcia, E.; Kayser, F. J. Am. Chem. Soc.
1993, 115, 9276-9282.
(15) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457-2483.
(16) (a) Tamao, K.; Sumitani, K.; Kumada, M. J. Am. Chem. Soc. 1972, 94,
4374-4376. (b) Corriu, R. J. P.; Masse, J. P. J. Chem. Soc., Chem.
Commun. 1972, 144a. (c) Kumada, M. Pure Appl. Chem. 1980, 52, 669-
679.
(5) Matheron, M. E.; Porchas, M. Plant Dis. 2004, 88, 665-668.
(6) Poetsch, E. Kontakte 1988, 2, 15-28.
(7) Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem. ReV.
2002, 102, 1359-1469.
(8) (a) Smith, M. B.; March, J. AdVanced Organic Chemistry, 4th ed.; Wiley:
New York, 1992; p 539. (b) Kovacic, P.; Jones, M. B. Chem. ReV. 1987,
87, 357-379.
(9) (a) Gomberg, M.; Bachmann, W. E. J. Am. Chem. Soc. 1924, 42, 2339-
2343. (b) Smith, M. B.; March, J. AdVanced Organic Chemistry, 4th ed.;
Wiley: New York, 1992; pp 715-717.
(10) (a) Ullman, F; Bielecki, J. Chem. Ber. 1901, 34, 2174-2185. (b) Hassan,
J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem. ReV. 2002,
102, 1359-1469.
9
4824
J. AM. CHEM. SOC. 2007, 129, 4824-4833
10.1021/ja068993+ CCC: $37.00 © 2007 American Chemical Society

Biaryl Synthesis
A R T I C L E S
Scheme 1. Traditional Biaryl Syntheses
we saw little opportunity to also use this metal as the catalyst
for the cross-coupling step.22 Here, palladium seemed to be a
more promising candidate, being known to efficiently mediate
a large number of two-electron cross-coupling reactions.
A possible reaction pathway for the desired transformation
is outlined in Scheme 3. The reaction of the aryl carboxylic
acid with the copper catalyst would initially follow the proposed
pathway for protodecarboxylation reactions, wherein the copper
derivative is believed to coordinate to the carboxylate oxygen,
shift to the aryl π-system, and insert into the C-C(O) bond
under extrusion of CO2 to form a stable aryl-copper interme-
diate.20b In parallel, the aryl halide should oxidatively add to
the palladium catalyst. The arylcopper species would then
transfer its aryl group to the palladium under formation of a
copper halide, and finally, the desired biaryl would be released,
regenerating the initial palladium species and resuming the
catalytic cycle. In principle, the copper halide should be able
to react with alkali metal carboxylates under ligand exchange,
so that a stoichiometric amount of copper is not required.
We recently disclosed the viability of this concept along with
a few examples in a preliminary communication.23 In this full
paper we give a detailed report of the catalyst development and
the exploration of scope and limitations of the new transforma-
tion, as well as providing many new examples that reflect further
progress in this field. Two alternative protocols for the biaryl
formation are disclosed, one of which proceeds at 160 °C and
is catalytic in palladium and for a steadily increasing number
of substrates also in copper, whereas the other involves a
stoichiometric amount of copper(II) carbonate as the base but
operates at a lower temperature (120 °C).
coupling of arylboronic acids is probably most widely used,
both in laboratory and industrial biaryl syntheses.17 Over the
last decades, it has continuously been improved and reached
an impressive level of performance.18
However, even the Suzuki-Miyaura reaction suffers from a
fundamental drawback common to all related catalytic cross-
couplings of aryl nucleophiles and electrophiles: It requires the
use of stoichiometric amounts of an expensive organometallic
compound, in this case a boronic acid. Like most other
organometallic carbon nucleophiles applied in cross-coupling
reactions, this must be prepared from sensitive precursors under
elaborate anaerobic conditions.19 For this reason, the formation
of the organometallic coupling partner is often more difficult
than the actual cross-coupling, especially when performed on
an industrial scale. This issue is illustrated below for the
synthesis of a Boscalid intermediate at BASF (Scheme 2, top),
currently one of the largest industrial applications of the
Suzuki-Miyaura reaction (ca. 1000 t/a).
In contrast to organometallic compounds, metal salts of
aromatic carboxylic acids are stable against air and water and
easily available at low cost. As the extrusion of CO2 from such
compounds should lead to the formation of organometallic
species, we imagined that a combination of this step with a
catalytic cross-coupling with an aryl halide could give a
particularly attractive biaryl synthesis (Scheme 2, bottom). The
main challenge in the design of such a process was that metal
salts of aromatic carboxylates require extreme temperatures to
lose CO2, and that under such conditions, the resulting aryl-
metal species are likely to undergo a fast protonation by the
surrounding medium to give the corresponding arenes before
they can be successfully coupled with aryl electrophiles.20
In order to reach our goal of a decarboxylative cross-coupling,
we needed to design an efficient catalyst system with the dual
ability to facilitate the strongly endothermic extrusion of carbon
dioxide from aryl carboxylates to form stable aryl-metal
compounds, and to mediate the selective cross-coupling of these
species with aryl electrophiles. Copper appeared to be the metal
of choice for the decarboxylation step, as it is widely used in
protodecarboxylation procedures.21 However, anticipating the
known complications of Ullmann-type couplings such as low
selectivities for the heterocoupling and low catalyst productivity,
Results and Discussion
Development of the Decarboxylative Cross-Coupling Meth-
odology. As the model reaction for our screening experiments,
we selected the cross-coupling of 2-nitrobenzoic acid (10a) with
4-bromochlorobenzene to form 2-nitro-4′-chlorobiphenyl; not
only is this reaction of particular commercial interest as a key
intermediate in the synthesis of Boscalid (see Figure 1),5 but it
also allows an easy detection of all reactants, products, and
byproducts by gas chromatography (Scheme 4).
Selected results from our screening experiments are sum-
marized in Table 1. With a monometallic palladium catalyst,
all attempts failed to achieve any reaction turnover (Entry 1).
This was not particularly surprising, as known palladium(II)-
mediated decarboxylations, e.g., in Heck-type reactions of aryl
carboxylic acids with olefins or of aryl halides with pyrrole-
carboxylic acids, involve completely different mechanisms that
cannot come into play in our model reaction.24 Without
palladium but using a stoichiometric amount of copper, the
desired product could not be detected under various conditions
at temperatures below 200 °C (Entry 2). However, when the
carboxylic acid was deprotonated with a stoichiometric amount
of CuCO3 and reacted with the aryl bromide in the presence of
(17) Maureen Rouhi, A. Chem. Eng. News 2004, 82, 49-58.
(18) (a) Marion, N.; Navarro, O.; Mei, J.; Stevens, E. D.; Scott, N. M.; Nolan,
S. P. J. Am. Chem. Soc. 2006, 128, 4101-4111. (b) Billingsley, K. L.;
Anderson, K. W.; Buchwald, S. L. Angew. Chem., Int. Ed. 2006, 45, 3484-
3488.
(19) Diederich, F.; Stang P. J.; Eds. Metal-catalyzed Cross-Coupling Reactions;
Wiley-VCH, Weinheim, 1998.
(22) For a related Ullmann-type reaction, see e.g. ref 20c.
(23) (a) Goossen, L. J.; Deng, G.; Levy, L. M. Science 2006, 313, 662-664.
(b) Goossen, L. J.; Deng, G. Patent pending, filing number PCT-DE2006-
001014 (2005).
(20) (a) Cohen, T.; Schambach, R. A. J. Am. Chem. Soc. 1970, 92, 3189-
3190. (b) Cohen, T.; Berninger, R. W.; Wood, J. T. J. Org. Chem. 1978,
43, 837-848. (c) Nilsson, M. Acta Chem. Scand. 1966, 20, 423-25.
(21) Smith, M. B.; March, J. AdVanced Organic Chemistry, 4th ed.; Wiley: New
York, 1992; pp 563-564.
(24) (a) Peschko, C.; Winklhofer, C.; Steglich, W. Chem. Eur. J. 2000, 6, 1147-
1152. (b) Tanaka, D.; Romeril, S. P.; Myers, A. G. J. Am. Chem. Soc.
2005, 127, 10323-10333. (c) Forgione, P.; Brochu, M.-C.; St-Onge, M.;
Thesen, K. H.; Bailey, M. D.; Bilodeau, F. J. Am. Chem. Soc. 2006, 128,
11350-11351.
9
J. AM. CHEM. SOC. VOL. 129, NO. 15, 2007 4825

A R T I C L E S
Goossen et al.
Scheme 2. Biaryl Synthesis from Aryl Halides via Boronic Acids and from Carboxylic Acids
Scheme 3. Proposed Mechanism for a Decarboxylative Biaryl
Synthesis
Å molecular sieves directly in the reaction mixture was more
practical and suppressed the protodecarboxylation just as
effectively, so that satisfactory yields were achieved with either
method (Entry 8). The decarboxylation step could also be
mediated by silver carbonate as an alternative to copper
carbonate (Entry 9), but due to the high price of this metal, we
did not further investigate this option and instead focused on
optimizing the cross-coupling catalyst. A beneficial effect was
observed for the addition of phosphines as ligands for the
palladium; among them, diphenyl isopropylphosphine proved
to have the ideal steric and electronic properties (Entries 10-
13). N-Methylpyrrolidine (NMP) was the best solvent, but the
reaction could also be performed in other polar aprotic media
(Entries 14-17). We were pleased to find that the model
reaction proceeded in excellent selectivity and almost quantita-
tive conversion under optimized conditions, consisting of
stoichiometric amounts of CuCO3 and KF, an excess of
powdered molecular sieves, and 2 mol % of a Pd(acac)2/P(i-
Pr)Ph2 catalyst in an NMP solution at 120 °C.
Scheme 4. Products and Observed Byproducts for the Model
Reaction
Following the proposed mechanism (Scheme 3), the copper
salt should be regenerated after each transmetalation step, so
that a catalytic amount should theoretically suffice. However,
when we tried to replace some of the CuCO3 by K2CO3, the
yields dropped to below the amount of copper employed (Entry
18). Raising the temperature from 120 °C or prolonging the
reaction time did not change this, and in either case we observed
a color shift from green to brown, indicative of a partial
reduction of Cu(II) to Cu(I). A control experiment revealed that
at 160 °C, the reduction of the copper by the NMP solvent was
complete within less than 1 h. This led us to conclude that a
reaction protocol catalytic in both metals would only be possible
with more stable but less effective Cu(I) complexes, at the
expense of an increased reaction temperature. However, even
at 160 °C, stoichiometric amounts of simple copper(I) salts gave
only very low conversions (Entries 19, 20). A reaction catalytic
in copper appeared to be out of reach until we discovered that
chelating bipyridine derivatives dramatically enhanced the
decarboxylation activity of the copper catalyst (Entries 21-
23). In the presence of bipyridine as the ligand for both copper
and palladium, turnover was accomplished for the first time
using substoichiometric amounts of copper, and with 3%
phenanthroline as the ligand, 1% CuI and 0.5% Pd(acac)2
sufficed for near-quantitative coupling in small-scale experi-
ments (Entries 22, 23).
a catalytic amount of palladium at a temperature as low as 120
°C, small amounts of the desired biaryl 7aa were detected along
with some arene 11a and the homocoupling products 12a and
14a (Entry 3). While modifications of the palladium source had
only little influence on the reaction outcome (Entry 4), the
addition of metal salts, particularly of alkali metal fluorides,
significantly facilitated the reaction turnover, presumably due
to an intermediate formation of ArC(O)OCuF, which seems to
lower the decarboxylation barrier (Entries 5-7). This is in good
agreement with the previously described finding that in the
pyrolysis of Cu(II) benzoate, only one of the two carboxyl
groups coordinated to the copper extrudes CO2, leading to the
formation of phenyl benzoate as an important byproduct.25
At this stage of our reaction development, protodecarboxy-
lation to nitrobenzene (11a) became the main side reaction, so
that we sought ways to efficiently remove water from the
reaction mixture. Since the reaction temperature exceeded 100
°C, the water formed in the decarboxylation step mostly
evaporated from the reaction medium and condensed in a cooler
part of the vessel. Drying was clearly more effective when fitting
the reaction vessel with a Soxhlet apparatus filled with molecular
sieves, leading to a significant enhancement of the yields. For
small-scale applications, suspending an excess of powdered 3
This optimized protocol could be easily scaled up from
millimolar to molar quantities without a decrease in yields. On
the contrary, when performed on preparative scale, its efficiency
could be further enhanced using a more elaborate reaction setup
consisting of a round-bottom flask equipped with a Soxhlet
apparatus filled with molecular sieves. The flask was charged
with purified potassium 2-nitrobenzoate and 4-bromotoluene in
a 1:1 ratio as a concentrated solution in a toluene/quinoline
(25) Kaeding, W. W.; Kerlinger, H. O.; Collins, G. R. J. Org. Chem. 1965, 30,
3754-3759.
9
4826 J. AM. CHEM. SOC. VOL. 129, NO. 15, 2007

Biaryl Synthesis
A R T I C L E S
Table 1. Development of Decarboxylative Cross-Coupling Reaction Conditionsa
entry
catalyst
ligand
base
additives
T (°
C)
solvent
7aa (%)
1
2
3
4
5
6
7
8
2% Pd(acac)2
6% PPh3
6% PPh3
6% PPh3
6% PPh3
6% PPh3
6% PPh3
6% PPh3
6% PPh3
K2CO3
CuCO3
CuCO3
CuCO3
CuCO3
CuCO3
CuCO3
CuCO3
Ag2CO3
CuCO3
CuCO3
CuCO3
CuCO3
CuCO3
CuCO3
CuCO3
CuCO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
-
-
-
-
-
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
160
160
160
160
150
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
DMSO
DMPU
mesitylene
diglyme
NMP
NMP
NMP
NMP
NMP
0
0
5
-
2% Pd(acac)2
2% PdCl2
2% Pd(acac)2
2% Pd(acac)2
2% Pd(acac)2
2% Pd(acac)2
2% Pd(acac)2
2% Pd(acac)2
2% Pd(acac)2
2% Pd(acac)2
2% Pd(acac)2
2% Pd(acac)2
2% Pd(acac)2
2% Pd(acac)2
2% Pd(acac)2
2% Pd(acac)2, 5% CuCO3
2% Pd(acac)2, 120% CuI
2% Pd(acac)2, 120% CuI
2% Pd(acac)2, 120% CuI
2% Pd(acac)2, 30% CuI
0.5% Pd(acac)2, 1% CuI
0.03% Pd(acac)2, 0.3% Cu*
3
KBr
14
16
32
84
47
76
60
35
98
69
62
0
NaF
KF
KF/3 Å MS
KF/3 Å MS
KF/3 Å MS
KF/3 Å MS
KF/3 Å MS
KF/3 Å MS
KF/3 Å MS
KF/3 Å MS
KF/3 Å MS
KF/3 Å MS
KF/3 Å MS
3 Å MS
9
6% PPh3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24b
3% BINAP
6% P(Cy)3
10% bipyridine
6% P(i-Pr)Ph2
6% P(i-Pr)Ph2
6% P(i-Pr)Ph2
6% P(i-Pr)Ph2
6% P(i-Pr)Ph2
6% P(i-Pr)Ph2
6% P(i-Pr)Ph2
6% P(i-Pr)Ph2
10% bipyridine
30% bipyridine
3% phenanthr
-
40
4
5
3 Å MS
3 Å MS
3 Å MS
3 Å MS
22
72
78
98
7ac 92
NMP
toluene/quinoline
-
a Conditions: 1.00 mmol 4-bromochlorobenzene, 1.50 mmol 2-nitrobenzoic acid, 1.50 mmol base (1.20 mmol for K2CO3), 1.50 mmol additive (500 mg
for molecular sieves ) MS), 24 h. Conversions were determined by GC analysis using n-tetradecane as the internal standard. b Conditions: 80.0 mmol
4-bromotoluene, 80.0 mmol potassium 2-nitrobenzoate, (1,10-phenanthroline)bis (triphenylphosphine)copper(I) nitrate (Cu*) as cocatalyst/azeotropic removal
of water, isolated yield.
mixture. After addition of the catalyst, part of the solvent was
distilled off while azeotroping off traces of water until a constant
boiling temperature of 150 °C was reached. Under these
conditions, the catalyst loading could be reduced to 0.03% Pd
and 0.3% Cu in the form of commercially available (1,10-
phenanthroline)bis(triphenylphosphine)copper(I) nitrate. The
product was isolated in an impressive 92% yield and >99%
purity after aqueous workup and Kugelrohr distillation (Entry
24).
decarboxylation and cross-coupling steps is crucial to achieve
high yields of the desired product and to avoid the undesired
byproducts 12 and 14 (Scheme 4). In order to design effective
catalyst systems for a range of carboxylic acids, we were
interested in getting an idea of their relative activity toward
decarboxylation in comparison to our model substrate 2-ni-
trobenzoic acid. Table 3 summarizes the results obtained for
the decarboxylation step examined separately from the cross-
coupling for a range of acids, in the absence of the Pd catalyst
and aryl halide, but otherwise under conditions similar to those
of the decarboxylative cross-coupling. As no base was added,
protons were amply available allowing an easy formation of
the corresponding arenes 11 from the intermediate arylcopper
species (see Table 3).
Scope with Regard to the Halide Substrate. We next set
out to explore the generality of the reaction with regard to the
aryl halide coupling partner and were pleased to find that both
reaction protocols are broadly applicable to the coupling of a
wide array of aryl bromides with 2-nitrobenzoic acid (10a)
(Table 2). Both electron-rich and electron-poor derivatives were
successfully converted, and a broad range of functional groups
including esters, ethers, aldehydes, ketones, nitriles, thioethers,
and even nitrogen-containing heterocycles were tolerated. Steri-
cally demanding substrates could also be coupled in good yields.
Moreover, the reaction is not limited to aryl bromides but can
also be performed with aryl iodides and even aryl chlorides using
the same catalyst system (Table 2, last three entries)
We were excited to find that with our most effective catalyst
system consisting of Cu2O/phenanthroline in a 1:3 mixture of
quinoline and NMP, a broad range of carboxylic acids smoothly
decarboxylated at a sufficiently high rate (Table 3, first data
column). This led us to conclude that there is no intrinsic
limitation to the applicability of the decarboxylative cross-
coupling reaction with respect to the carboxylate substrate.
However, the addition of a halide salt, as would inevitably form
in such a process (see Scheme 3), was found to substantially
retard the decarboxylation step (Table 3, second and third data
columns). For 2-nitrobenzoic acid (10a), already an equimolar
amount of potassium bromide with regard to the copper slightly
slowed down the decarboxylation process with one of our earlier
catalysts that contained quinoline as the only copper ligand, and
adding excess bromide led to a further drop in conversion (Table
3, numbers in brackets). Using phenanthroline as the ligand,
Investigation of the Decarboxylation Step. While varying
the aryl halide substrate was surprisingly easy, extending the
reaction from 2-nitrobenzoic acid (10a) to other carboxylic acids
initially proved to be troublesome:23 A notable but limited range
of carboxylic acids could be converted in the presence of
stoichiometric amounts of copper, but approaches involving
catalytic copper long remained limited to 2-nitrobenzoic acids.
This was not unexpected, as a good balance of the rates of the
9
J. AM. CHEM. SOC. VOL. 129, NO. 15, 2007 4827

A R T I C L E S
Goossen et al.
Table 2. Scope of the Cross-Coupling Reaction with Regard to the Aryl Halide Substratea
a Conditions: Method A: 1.00 mmol aryl bromide, 1.50 mmol carboxylic acid, 0.02 mmol Pd(acac)2, 0.06 mmol P(i-Pr)Ph2, 1.50 mmol CuCO3, 1.50
mmol KF, 500 mg ground 3 Å MS, 3 mL NMP, 120 °C, 24 h, isolated yields. Method B: 1 mmol aryl bromide, 1.50 mmol carboxylic acid, 0.01 mmol
Pd(acac)2, 0.03 mmol CuI, 0.05 mmol 1,10-phenanthroline, 1.20 mmol K2CO3, 250 mg 3 Å MS, 1.5 mL NMP, 160 °C, 24 h, isolated yields.
the conversion remained unaffected by the presence of bromide,
demonstrating the superiority of this catalyst system and
explaining why 2-nitrobenzoic acid (10a) is such a good
substrate for the decarboxylative cross-coupling.
decarboxylation using catalytic amounts of a copper phenan-
throline system.
The second data column of Table 3 shows that the carboxylic
acids tested can be roughly divided into two categories: Some
only decarboxylate with the phenanthroline copper catalyst in
the absence of bromide ions and will thus probably require a
stoichiometric amount of copper in the cross-coupling process,
while others tolerate the presence of halides so that catalytic
amounts of copper can be expected to suffice. Among the
substrates that are least affected by the presence of halides are
many ortho-substituted or heterocyclic carboxylic acids, pre-
sumably because they are able to coordinate to the copper in a
bidentate fashion. This may help them to compete successfully
This trend was amplified in the case of 2-cyanobenzoic acid
(10b), which is one of the least reactive compounds that we
were able to cross-couple successfully. Here, the quinoline
system no longer mediated the decarboxylation when a halide
salt was present, while the phenanthroline system retained a
sufficient level of activity. For even less reactive acids such as
4-nitrobenzoic acid (10c), the rates were still too low even with
our best ligand system, so that it appeared unlikely that this
carboxylic acid could be successfully cross-coupled under
9
4828 J. AM. CHEM. SOC. VOL. 129, NO. 15, 2007

Biaryl Synthesis
A R T I C L E S
Table 3. The Decarboxylation Step and the Influence of Bromide
efficiently decarboxylate in the presence of KBr. For some
substrates for which the process catalytic in both Pd and Cu
did not give satisfactory yields, reaction turnover was still
achieved in the presence of stoichiometric amounts of copper
(Table 4, last five entries). We restricted the number of examples
for the less desirable stoichiometric processes (method A, C),
as ongoing catalyst development in our group seems to indicate
that improved copper catalyst will allow a further extension of
the substrate scope for the protocol catalytic in both metals.
However, the fact that even the notoriously unreactive, electron-
rich 4-methoxybenzoic acid (10r) could be coupled in moderate
yield shows that a process stoichiometric in copper may turn
out to have a considerable scope.
Ionsa
yield (%)b at the following
rel. amount of KBr:
Ar (product no.)
0%
15%
100%
2-NO2-C6H4-(11a)
2-CN-C6H4-(11b)
4-NO2-C6H4-(11c)
2-CHO-C6H4-(11d)
2-MeCO-C6H4-(11e)
2-iPrCO2-C6H4-(11f)
2-Et2NCO-C6H4-(11g)
2-MeSO2-C6H4-(11h)
2-F-C6H4-(11i)
2-MeO-C6H4-(11j)
2-PhNH-C6H4-(11k)
2-CF3-C6H4-(11l)
2-MeCONH-C6H4-(11m)
2-naphthalene-(11n)
2-thiophene-(11o)
Ph-CH2dCH2-(11p)
3-CN-C6H4-(11q)
4-MeO-C6H4-(11r)
3-thiophene-(11s)
100 (95)
40 (15)
52 (8)
67
79
70
68
54
75
28
96
50
48
61
38
40
72
23
100 (95)
95 (60)
10 (0)
0 (0)
25 (10)
25 (0)
67
76
70
61
43
75
7
23
15
0
24
34
40
24
0
Summary and Outlook
A decarboxylative cross-coupling of arenecarboxylates with
aryl halides mediated by a Cu/Pd catalyst was developed as a
new strategy for biaryl synthesis. Its key advantage in com-
parison to existing protocols is that it draws on readily available
carboxylic acids as sources of aryl nucleophiles in place of
expensive organometallic compounds. Two alternative protocols
were developed, one with a stoichiometric and the other with a
catalytic amount of copper, both of them broadly applicable
with regard to the aryl halide substrate and a growing number
of carboxylic acid coupling partners. In the protocol catalytic
in copper, best results were obtained with ortho-substituted or
heterocyclic carboxylic acids, which are able to coordinate to
copper in a chelating fashion allowing them to successfully
compete with halides for coordination sites. Current work is
directed toward the development of more active catalyst systems
with ligands designed to induce a stronger preference of the
copper component for carboxylate ions over halides and,
alternatively, to the use of aryl sulfonates as halide-free coupling
partners. The goal is to extend the scope of the decarboxylative
cross-coupling, hopefully to the entire range of aromatic, vinylic,
and heteroaromatic acids.
44
7
a Conditions: 1.00 mmol benzoic acid derivative, 0.075 mmol Cu2O,
0.15 mmol 1,10-phenanthroline, 0.5 mL quinoline, 1.5 mL NMP, 170 °C,
6 h. Conversions were determined by GC analysis using n-tetradecane as
the internal standard. Part of the product remained bound to the copper
and is not included in the reported yield b Numbers in brackets correspond
to reactions performed without phenanthroline.
with the halide for the required coordination site at the copper.
Following this hypothesis, the key to achieving a generally
applicable process catalytic in both metals should be to induce
a stronger preference of the copper for carboxylate over bromide
ions by tuning its ligand environment.
Scope with Regard to the Carboxylate Substrate. With
gradual improvements of the copper catalyst, we were already
able to extend the range of carboxylic acids that decarboxylate
in the presence of bromide salts from 2-nitrobenzoic acids,
which decarboxylate even in the presence of simple CuI, initially
to carboxylic acids with other strongly coordinating groups in
ortho-position that increase the copper-ligating quality of the
carboxylate substrate (2-acyl, 2-formyl), later to carboxylic acids
with weakly coordinating ortho-substituents (2-methoxy, 2-cy-
ano), and finally to vinylic or heterocyclic derivatives (cinnamic,
thiophenecarboxylic acids). This seems to be the performance
limit when employing phenanthroline as the copper ligand, but
ongoing work indicates that the use of more elaborate copper
ligands leads to a further substantial increase in decarboxylation
activity, especially for meta- and para-substituted carboxylic
acids.
On the basis of the decarboxylation results in Table 3, we
probed the scope of the overall process with regard to the
carboxylic acid substrate. Selected results are summarized in
Table 4. Previously, we needed to optimize the reaction for each
substrate individually and, as a result, reported multiple alterna-
tive procedures. Now, we have identified a single protocol
involving 10% of a Cu(I)Br/phenanthroline catalyst along with
3% palladium bromide (method B′) that is applicable to a
remarkable range of derivatives, among them all derivatives that
Experimental Section
General Methods. Reactions were performed in oven-dried glass-
ware under a nitrogen atmosphere containing a Teflon-coated stirrer
bar and dry septum, unless otherwise specified. For the exclusion of
atmospheric oxygen from the reaction media, three freeze-pump-thaw
cycles were preformed before the reagents were mixed. Solvents were
purified by standard procedures prior to use. All reactions were
monitored by GC using n-tetradecane as an internal standard. Response
factors of the products with regard to n-tetradecane were obtained
experimentally by analyzing known quantities of the substances. GC
analyses were carried out using an HP-5 capillary column (Phenyl
Methyl Siloxane 30 m × 320 × 0.25, 100/2.3-30-300/3) and a time
program beginning with 2 min at 60 °C followed by 30 °C/min ramp
to 300 °C and then 3 min at this temperature. Column chromatography
was performed using a Combi Flash Companion-Chromatography-
System (Isco-Systems) and RediSep packed columns (12 g). NMR
spectra were obtained on Bruker AMX 400 systems using CDCl3 as
solvent, with proton and carbon resonances at 400 and 100 MHz,
respectively. Mass spectral data were acquired on a GC-MS Saturn
2100 T (Varian).
Biaryl Synthesis from Copper(II) Nitrobenzoate (Method A,
Table 1, 2, and 4). An oven-dried 20 mL crimp top vial equipped
with a septum cap was charged with 2-nitrobenzoic acid (10a) (250
mg, 1.50 mmol), CuCO3 (185 mg, 1.50 mmol), and NMP (1 mL). The
resulting mixture was stirred for 0.5 h at 120 °C, then the solvent was
evaporated under reduced pressure to remove most of the reaction water.
9
J. AM. CHEM. SOC. VOL. 129, NO. 15, 2007 4829

A R T I C L E S
Goossen et al.
Table 4. Substrate Scope of the Cross-Coupling Reaction
Conditions: Methods A and B: see Table 2; method B′: 1.20 mmol 4-bromotoluene (4c), 1.00 mmol carboxylic acid, 0.03 mmol PdBr2, 0.10 mmol
CuBr, 0.10 mmol 1,10-phenanthroline, 1.00 mmol K2CO3, 250 mg ground 3 Å MS, 1.5 mL NMP, 0.5 mL quinoline, 170 °C, 24 h, isolated yields; method
C: 1.00 mmol aryl bromide, 1.30 mmol carboxylic acid, 0.02 mmol Pd(acac)2, 1.20 mmol CuI, 0.10 mmol 2,2′-bipyridine, 1.20 mmol K2CO3, 500 mg 3 Å
MS, 3 mL NMP, 160 °C, 24 h, isolated yields. a Using 4-bromochlorobenzene (4a) as coupling partner. b At 150 °C. c At 160 °C.
Subsequently, the reaction vessel was charged with Pd(acac)2 (6.1 mg,
0.02 mmol), iso-propyldiphenylphosphine (13.7 mg, 0.06 mmol),
potassium fluoride (87 mg, 1.50 mmol), and pulverized 3 Å molecular
sieves (500 mg). After the vessel was flushed with alternating vacuum
and nitrogen purge cycles, a solution of the corresponding aryl halide
(4a-u, 4′a,b, 4′′c) (1.00 mmol) and the internal standard n-tetradecane
(50 µL) in NMP (3 mL) was added Via syringe. The resulting mixture
was stirred at 120 °C for 24 h, poured into aqueous HCl (1 N, 20 mL),
and extracted repeatedly with 20 mL portions of ethyl acetate. The
combined organic layers were washed with water and brine, dried over
MgSO4, and filtered, and the volatiles were removed in Vacuo. The
residue was purified by column chromatography (SiO2, ethyl acetate/
hexane gradient), yielding the corresponding biaryl.
mg, 0.03 mmol), palladium acetylacetonate (3.0 mg, 0.01 mmol), 1,-
10-phenanthroline (9 mg, 0.05 mmol), and pulverized 3 Å molecular
sieves (250 mg) were added, and the reaction vessel was evacuated
and flushed with nitrogen three times. Subsequently, a solution of the
corresponding aryl halide (4a-u, 4′a,b, 4′′c) (1.00 mmol) and the
internal standard n-tetradecane (50 µL) in NMP (1.5 mL) was added
Via syringe. The resulting mixture was stirred at 160 °C for 24 h, diluted
with aqueous HCl (1 N, 10 mL), and extracted repeatedly with 20 mL
portions of ethyl acetate. The combined organic layers were washed
with water and brine, dried over MgSO4, and filtered, and the volatiles
were removed in Vacuo. The residue was purified by column chroma-
tography (SiO2, ethyl acetate/hexane gradient), yielding the correspond-
ing biaryl.
Biaryl Synthesis Using a Catalytic Amount of Copper (Method
B, Table 2 and 4). An oven-dried 20 mL vessel was charged with
2-nitrobenzoic acid (10a) (250 mg, 1.50 mmol), potassium carbonate
(167 mg, 1.20 mmol), and NMP (1 mL). The resulting mixture was
stirred for 0.5 h at 120 °C, and then the solvent was evaporated under
reduced pressure to remove the reaction water. Copper(I) iodide (5.7
Method B′ (Table 4). Method B′ is analogous to Method B but
with a higher loading of a modified catalyst and performing the reaction
at 170 °C. The following amounts were used: carboxylic acid (10d-
r) (1.00 mmol), potassium carbonate (138 mg, 1.00 mmol), copper(I)
bromide (14.3 mg, 0.10 mmol), palladium bromide (8.0 mg, 0.03
mmol), 1,10-phenanthroline (18.0 mg, 0.10 mmol), pulverized 3 Å
9
4830 J. AM. CHEM. SOC. VOL. 129, NO. 15, 2007

Biaryl Synthesis
A R T I C L E S
molecular sieves (250 mg), and a solution of 4-bromotoluene (4c) (205
mg, 1.20 mmol) and the internal standard n-tetradecane (50 µL) in a
mixture of NMP (1.5 mL) and quinoline (0.5 mL). The residue was
again purified by column chromatography (SiO2, ethyl acetate/hexane
gradient), yielding the corresponding biaryl.
(250 mg, 1.50 mmol) and 4-iodotoluene (4′′c) (218 mg, 1.00 mmol),
to give 179 mg (84%) following Method A, and 81 mg (38%) following
Method B.
Synthesis of 4-Methoxy-2′-nitrobiphenyl (7ad). Compound 7ad
was prepared following Method A from 2-nitrobenzoic acid (10a) (250
mg, 1.50 mmol) and 4-bromoanisole (4d) (187 mg, 1.00 mmol),
yielding 7ad as a yellow oil (181 mg, 79%). The spectroscopic data
(NMR, GC-MS) matched those reported in the literature for 4-methoxy-
2′-nitrobiphenyl [CAS: 20013-55-2]. Compound 7ad was also
prepared using the same amounts following Method B in 68% yield
(156 mg).
Biaryl Synthesis Using a Stoichiometric Amount of Copper
(Method C, Table 4). Method C is analogous to Method B but with
a stoichiometric amount of copper. The following amounts were used:
carboxylic acid (10) (1.30 mmol), 4-bromotoluene (4c) (171 mg, 1.00
mmol), palladium acetylacetonate (5.3 mg, 0.02 mmol), copper(I) iodide
(286 mg, 1.50 mmol), 2,2′-bipyridine (15.6 mg, 0.10 mmol), potassium
carbonate (167 mg, 1.20 mmol), pulverized 3 Å molecular sieves (250.0
mg), and a solution of 4-bromotoluene (4c) (205 mg, 1.20 mmol) and
the internal standard n-tetradecane (50 µL) in NMP (3 mL).
Synthesis of 4-Methylthio-2′-nitrobiphenyl (7ae). Compound 7ae
was prepared following Method A from 2-nitrobenzoic acid (10a) (250
mg, 1.50 mmol) and 1-bromo-4-methylsulfanyl benzene (4e) (203 mg,
1.00 mmol), yielding 7ae as a yellow solid (201 mg, 82%). The
spectroscopic data (NMR, GC-MS) matched those reported in the
literature for 4-methylthio-2′-nitrobiphenyl [CAS: 911217-03-3]. Com-
pound 7ae was also prepared using the same amounts following Method
B in 98% yield (240 mg).
Large Scale Procedure for the Synthesis 4-Methyl-2′-nitrobi-
phenyl (7ac) (Table 1, Entry 24). An oven-dried flask was equipped
with an internal thermometer and a Soxhlet apparatus filled with
molecular sieves and charged with purified potassium 2-nitrobenzoate
(16.4 g, 80.00 mmol), (1,10-phenanthroline)bis-(triphenyl-phosphine)-
copper(I) nitrate (199 mg, 0.24 mmol), and palladium acetyl-acetonate
(7.3 mg, 0.024 mmol). After the vessel was flushed with alternating
vacuum and nitrogen purge cycles, a solution of 4-bromotoluene (4c)
(13.7 g, 80.00 mmol) in a mixture of toluene (60 mL) and quinoline
(60 mL) was added. The vessel was lowered into an oil bath preheated
to 175 °C, and part of the solvent was distilled off until the boiling
temperature remained constant at 150 °C. After the reaction mixture
was stirred for 24 h, it was allowed to cool to room temperature,
acidified with aqueous HCl (5 N, 100 mL), and extracted repeatedly
with toluene. The combined organic layers were washed with brine,
dried over MgSO4, and filtered. The volatiles were removed in Vacuo,
and the residue was purified by Kugelrohr distillation yielding 7ac (15.6
g, 92%) as a yellow oil.
Synthesis of 4-Acetyl-2′-nitrobiphenyl (7af). Compound 7af was
prepared following Method A from (250 mg, 1.50 mmol) and
4-bromoacetophenone (4f) (199 mg, 1.00 mmol), yielding 7af as a
yellow solid (208 mg, 86%). The spectroscopic data (NMR, GC-MS)
matched those reported in the literature for 4-acetyl-2′-nitrobiphenyl
[CAS: 5730-96-1]. Compound 7af was also prepared using the same
amounts following Method B in 57% yield (137 mg).
Synthesis of 4-(Ethoxycarbonyl)-2′-nitrobiphenyl (7ag). Com-
pound 7ag was prepared following Method A from 2-nitrobenzoic acid
(10a) (250 mg, 1.50 mmol) and 4-bromobenzoic acid ethyl ester (4g)
(229 mg, 1.00 mmol), yielding 7ag as a yellow solid (263 mg, 97%).
The spectroscopic data (NMR, GC-MS) matched those reported in the
literature for 4-(ethoxycarbonyl)-2′-nitrobiphenyl [CAS: 108621-65-
4]. Compound 7ag was also prepared using the same amounts following
Method B in 96% yield (260 mg).
Synthesis of 4-Chloro-2′-nitrobiphenyl (7aa). Compound 7aa was
prepared following Method A from 2-nitrobenzoic acid (10a) (250 mg,
1.50 mmol) and 4-bromochlorobenzene (4a) (191 mg, 1.00 mmol),
yielding 7aa as a yellow solid (216 mg, 96%). The spectroscopic data
(NMR, GC-MS) matched those reported in the literature for 4-chloro-
2′-nitrobiphenyl [CAS: 6271-80-3]. Compound 7aa was also prepared
using the same amounts following Method B in 99% yield (231 mg).
Synthesis of 4-Formyl-2′-nitrobiphenyl (7ah). Compound 7ah was
prepared following Method A from 2-nitrobenzoic acid (10a) (250 mg,
1.50 mmol) and 4-bromobenzaldehyde (4h) (185 mg, 1.00 mmol),
yielding 7ah as a yellow solid (212 mg, 93%). The spectroscopic data
(NMR, GC-MS) matched those reported in the literature for 4-formyl-
2′-nitrobiphenyl [CAS: 169188-17-4]. Compound 7ah was also
prepared using the same amounts following Method B in 78% yield
(177 mg).
Synthesis of 4-Chloro-2′-nitrobiphenyl (7aa) from 1,4-Dichlo-
robenzene (4′a). Compound 7aa was also prepared from 2-nitrobenzoic
acid (10a) (250 mg, 1.50 mmol) and 1,4-dichlorobenzene (4′a) (441
mg, 3.00 mmol) following Method B to give 154 mg (66%).
Synthesis of 2,4-Dimethyl-2′-nitrobiphenyl (7ai). Compound 7ai
was prepared following Method A from 2-nitrobenzoic acid (10a) (250
mg, 1.50 mmol) and 4-bromo-m-xylene (4i) (185 mg, 1.00 mmol),
yielding 7ai as a yellow solid (212 mg, 93%). The spectroscopic data
(NMR, GC-MS) matched those reported in the literature for 2,4-
dimethyl-2′-nitrobiphenyl [CAS: 911217-05-5]. Compound 7ai was
also prepared using the same amounts following Method B in 23%
yield (52 mg).
Synthesis of 4-Cyano-2′-nitrobiphenyl (7ab). Compound 7ab was
prepared following Method A from 2-nitrobenzoic acid (10a) (250 mg,
1.50 mmol) and 1-bromo-4-cyanobenzene (4b) (181 mg, 1.00 mmol),
yielding 7ab as a yellow solid (216 mg, 96%). The spectroscopic data
(NMR, GC-MS) matched those reported in the literature for 4-cyano-
2′-nitrobiphenyl [CAS: 75898-34-9]. Compound 7ab was also prepared
using the same amounts following Method B in 93% yield (208 mg).
Synthesis of 2-Methoxy-2′-nitrobiphenyl (7aj). Compound 7aj was
prepared following Method A from 2-nitrobenzoic acid (10a) (250 mg,
1.50 mmol) and 2-bromoanisole (4j) (187 mg, 1.00 mmol), yielding
7aj as a yellow oil (184 mg, 80%). The spectroscopic data (NMR,
GC-MS) matched those reported in the literature for 2-methoxy-2′-
nitrobiphenyl [CAS: 6460-92-0]. Compound 7aj was also prepared
using the same amounts following Method B in 30% yield (69 mg).
Synthesis of 4-Cyano-2′-nitrobiphenyl (7ab) from 1-Chloro-4-
cyanobenzene (4′b). Compound 7ab was also prepared from 2-ni-
trobenzoic acid (10a) (250 mg, 1.50 mmol) and 1-chloro-4-cyanoben-
zene (4′b) (137 mg, 1.00 mmol), to give 27 mg (12%) following Method
A, and 216 mg (96%) following Method B.
Synthesis of 4-Methyl-2′-nitrobiphenyl (7ac). Compound 7ac was
prepared following Method A from 2-nitrobenzoic acid (10a) (250 mg,
1.50 mmol) and 4-bromotoluene (4c) (171 mg, 1.00 mmol), yielding
7ac as a yellow oil (206 mg, 97%). The spectroscopic data (NMR,
GC-MS) matched those reported in the literature for 4-methyl-2′-
nitrobiphenyl [CAS: 70680-21-6]. Compound 7ac was also prepared
using the same amounts following Method B in 72% yield (153 mg).
Synthesis of 1-(9-Phenanthryl)-2-nitrobenzene (7ak). Compound
7ak was prepared following Method A from 2-nitrobenzoic acid (10a)
(250 mg, 1.50 mmol) and 9-bromophenanthrene (4k) (257 mg, 1.00
mmol), yielding 7ak as a yellow solid (257 mg, 86%). The spectro-
scopic data (NMR, GC-MS) matched those reported in the literature
for 1-(9-phenanthryl)-2-nitrobenzene [CAS: 911217-05-5]. Compound
7ak was also prepared using the same amounts following Method B
in 99% yield (299 mg).
Synthesis of 4-Methyl-2′-nitrobiphenyl (7ac) from 4-Iodotoluene
(4′′c). Compound 7ac was also prepared from 2-nitrobenzoic acid (10a)
9
J. AM. CHEM. SOC. VOL. 129, NO. 15, 2007 4831

A R T I C L E S
Goossen et al.
Synthesis of 4-Fluoro-2′-nitrobiphenyl (7al). Compound 7al was
prepared following Method A from 2-nitrobenzoic acid (10a) (250 mg,
1.50 mmol) and 4-bromo-fluorobenzene (4l) (175 mg, 1.00 mmol),
yielding 7al as a yellow oil (145 mg, 67%). The spectroscopic data
(NMR, GC-MS) matched those reported in the literature for 4-fluoro-
2′-nitrobiphenyl [CAS: 390-38-5]. Compound 7al was also pre-
pared using the same amounts following Method B in 97% yield
(211 mg).
Synthesis of 2′-Nitro-4-trifluoromethylbiphenyl (7am). Compound
7am was prepared following Method A from 2-nitrobenzoic acid (10a)
(250 mg, 1.50 mmol) and 4-bromo-trifluorotoluene (4m) (225 mg, 1.00
mmol), yielding 7am as a yellow oil (222 mg, 83%). The spectroscopic
data (NMR, GC-MS) matched those reported in the literature for 2′-
nitro-4-trifluoromethylbiphenyl [CAS: 189575-69-7]. Compound 7am
was also prepared using the same amounts following Method B in 93%
yield (248 mg).
Synthesis of 2-(2-Nitrophenyl)naphthalene (7an). Compound 7an
was prepared following Method A from 2-nitrobenzoic acid (10a) (250
mg, 1.50 mmol) and 2-bromo-naphthalene (4n) (206 mg, 1.00 mmol),
yielding 7an as a yellow solid (234 mg, 94%). The spectroscopic data
(NMR, GC-MS) matched those reported in the literature for 2-(2-
nitrophenyl)naphthalene [CAS: 94064-83-2]. Compound 7an was also
prepared using the same amounts following Method B in 94% yield
(233 mg).
Synthesis of 2,4′-Dinitrobiphenyl (7ao). Compound 7ao was
prepared following Method A from 2-nitrobenzoic acid (10a) (250 mg,
1.50 mmol) and 1-bromo-4-nitrobenzene (4o) (202 mg, 1.00 mmol),
yielding 7ao as a yellow solid (232 mg, 95%). The spectroscopic data
(NMR, GC-MS) matched those reported in the literature for 2,4′-
dinitrobiphenyl [CAS: 606-81-5]. Compound 7ao was also prepared
using the same amounts following Method B in 77% yield (156 mg).
Synthesis of 1-(2-Nitrophenyl)naphthalene (7ap). Compound 7ap
was prepared following Method A from 2-nitrobenzoic acid (10a) (250
mg, 1.50 mmol) and 1-bromo-naphthalene (4p) (207 mg, 1.00 mmol),
yielding 7ap as a yellow solid (220 mg, 88%). The spectroscopic data
(NMR, GC-MS) matched those reported in the literature for 1-(2-
nitrophenyl)naphthalene [CAS: 5415-59-8]. Compound 7ap was also
prepared using the same amounts following Method B in 97% yield
(241 mg).
Synthesis of 3-(2-Nitrophenyl)pyridine (7at). Compound 7as was
prepared following Method A from 2-nitrobenzoic acid (10a) (250 mg,
1.50 mmol) and 3-bromopyridine (4t) (158 mg, 1.00 mmol), yielding
7at as a yellow solid (19 mg, 10%). The spectroscopic data (NMR,
GC-MS) matched those reported in the literature for 3-(2-nitrophenyl)-
pyridine [CAS: 4253-80-9]. Compound 7at was also prepared using
the same amounts following Method B in 98% yield (196 mg).
Synthesis of 4-(2-Nitrophenyl)benzophenone (7au). Compound
7au was prepared following Method A from 2-nitrobenzoic acid (10a)
(250 mg, 1.50 mmol) and 4-bromobenzophenone (4u) (261 mg, 1.00
mmol), yielding 7au as a yellow solid (285 mg, 94%). Compound 7au
was also prepared using the same amounts following Method B in 99%
1
yield (300 mg). H NMR (300 MHz, CDCl3) δ) 7.89-7.95 (m, 1H),
7.84 (t, J ) 8.4 Hz, 4H), 7.62-7.66 (m, 1H), 7.55-7.59 (m, 1H), 7.40-
7.53 (m, 6H) ppm; 13C NMR (75 MHz, CDCl3): δ ) 196.0, 148.8,
141.6, 137.3, 137.0, 135.4, 132.6, 132.5, 131.7, 130.3, 130.0, 128.8,
128.3, 127.9, 124.3 ppm. HRMS (EI) for C19H13NO3, 303.089541, found
303.089823. MS (Ion trap, EI): m/z (%) ) 303 (39, [M+]), 226 (36),
152 (16), 105 (100), 77 (44).
Synthesis of 2-Cyano-4′-methylbiphenyl (7bc). Compound 7bc was
prepared following Method B′ from 2-cyanobenzoic acid (10b) (147
mg, 1.00 mmol) and 4-bromotoluene (4c) (205 mg, 1.20 mmol),
yielding 7bc as a white solid (65 mg, 34%). The spectroscopic data
(NMR, GC-MS) matched those reported in the literature for 2-cyano-
4′-methylbiphenyl [CAS: 114772-53-1]. Compound 7bc was also
prepared following Method C from 2-cyanobenzoic acid (10b) (191
mg, 1.30 mmol) and 4-bromotoluene (4c) (171 mg, 1.00 mmol),
yielding 7bc in 55% (106 mg).
Synthesis of 4′-Methyl-2-formylbiphenyl (7dc). Compound 7dc
was prepared following Method B′ from 2-carboxybenzaldehyde (150
mg, 1.00 mmol) and 4-bromotoluene (4c) (205 mg, 1.20 mmol),
yielding 7dc as a white solid (120 mg, 61%). The spectroscopic data
(NMR, GC-MS) matched those reported in the literature for 4′-methyl-
2-formylbiphenyl [CAS: 16191-28-9].
Synthesis of 2-Acetyl-4′-methylbiphenyl (7ec). Compound 7ec was
prepared following Method B′ from 2-acetylbenzoic acid (10e) (164
mg, 1.00 mmol) and 4-bromotoluene (4c) (205 mg, 1.20 mmol),
yielding 7ec as a white solid (144 mg, 69%). The spectroscopic data
(NMR, GC-MS) matched those reported in the literature for 2-acetyl-
4′-methylbiphenyl [CAS: 16927-79-0].
Synthesis of Isopropyl 4′-Methylbiphenyl-2-carboxylate (7fc).
Compound 7fc was prepared following Method B′ from isopropyl
phenyl 2-carboxylate (10f) (246 mg, 1.00 mmol) and 4-bromotoluene
(4c) (205 mg, 1.20 mmol), yielding 7fc as a white solid (129 mg, 51%).
1H NMR (400 MHz, CDCl3) δ ) 7.84-7.90 (m, 1H), 7.51-7.57 (m,
1H), 7.40-7.47 (m, 2H), 7.25-7.33 (m, 4H), 5.04-5.14 (m, 1H), 2.47
(s, 3H), 1.14 (d, J ) 6.2 Hz, 6H) ppm; 13C NMR (101 MHz, CDCl3)
δ ) 168.2, 142.2, 138.6, 136.6, 132.0, 130.6, 130.4, 129.3, 128.6, 128.5,
128.3, 126.7, 68.3, 21.3, 20.9 ppm. Anal. Calcd for C17H18O2: C, 80.3;
H, 7.1. Found: C, 80.3; H, 7.2. MS (Ion trap, EI): m/z (%) ) 254
(100, [M+]), 212 (22), 211 (20), 196 (18), 195 (55), 165 (27), 152
(16).
Synthesis of 2-Nitrobiphenyl (7aq). Compound 7aq was prepared
following Method A from 2-nitrobenzoic acid (10a) (250 mg, 1.50
mmol) and bromobenzene (4q) (157 mg, 1.00 mmol), yielding 7aq as
a yellow solid (170 mg, 85%). The spectroscopic data (NMR, GC-
MS) matched those reported in the literature for 2-nitrobiphenyl [CAS:
86-00-0]. Compound 7aq was also prepared using the same amounts
following Method B in 91% yield (181 mg).
Synthesis of 2-Nitro-4′-propylbiphenyl (7ar). Compound 7ar was
prepared following Method A from 2-nitrobenzoic acid (10a) (250 mg,
1.50 mmol) and 1-bromo-4-propylbenzene (4r) (199 mg, 1.00 mmol),
yielding 7ar as a yellow oil (228 mg, 95%). Compound 7ar was also
prepared using the same amounts following Method B in 62% yield
1
(148 mg). H NMR (400 MHz, CDCl3): δ ) 7.81 (dd, J ) 8.4, 1.2
Hz, 1H), 7.56-7.63 (m, 1H), 7.41-7.48 (m, 2H), 7.23 (s, 4H), 2.60-
2.65 (m, 2H), 1.63-1.72 (m, 2H), 0.97 (t, J ) 7.3 Hz, 3H) ppm; 13C
NMR (101 MHz, CDCl3): δ ) 149.3, 142.8, 136.2, 134.4, 132.1, 132.0,
131.8, 128.7, 128.6, 128.1, 128.0, 127.8, 127.6, 123.9, 37.8, 24.4, 14.0
ppm. HRMS (EI) for C15H15NO2, 241.110276, found 241.110025. MS
(Ion trap, EI): m/z (%) ) 241 (60, [M+]), 212 (57), 165 (100), 139
(12), 115 (13), 76 (7).
Synthesis of 2-(2-Nitrophenyl)pyridine (7as). Compound 7as was
prepared following Method A from 2-nitrobenzoic acid (10a) (250 mg,
1.50 mmol) and 2-bromopyridine (4s) (158 mg, 1.00 mmol), yielding
7as as a yellow oil (25 mg, 13%). The spectroscopic data (NMR, GC-
MS) matched those reported in the literature for 2-(2-nitrophenyl)-
pyridine [CAS: 4253-81-0]. Compound 7as was also prepared using
the same amounts following Method B in 53% yield (106 mg).
Synthesis of N,N-Diethyl-2-(4′-methylbiphenyl)carboxamide (7gc).
Compound 7gc was prepared following Method B′ from 2-(diethyl-
carbamoyl)benzoic acid (10g) (221 mg, 1.00 mmol) and 4-bromotoluene
(4c) (205 mg, 1.20 mmol), yielding 7gc as a white solid (119 mg, 45%).
1H NMR (600 MHz, CDCl3) δ ) 7.39-7.42 (m, 1H), 7.33-7.38 (m,
5H), 7.17 (d, J ) 7.9 Hz, 2H), 3.73 (dd, J ) 13.5, 6.7 Hz, 1H), 3.02
(dd, J ) 13.6, 6.8 Hz, 1H), 2.95 (dd, J ) 14.3, 7.2 Hz, 1H), 2.65 (dd,
J ) 14.3, 7.0 Hz, 1H), 2.36 (s, 3H), 0.91 (t, J ) 7.1 Hz, 3H), 0.73 (t,
J ) 7.1 Hz, 3H); 13C NMR (151 MHz, CDCl3) δ ) 170.7, 138.3, 137.3,
136.9, 136.3, 129.4, 129.0, 128.9, 128.7, 127.3, 127.0, 42.2, 38.3, 21.1,
13.4, 12.0 ppm. Anal. Calcd for C18H21NO: C, 80.9; H, 7.9; N, 5.2.
Found: C, 80.7; H, 7.8; N, 5.3. MS (Ion trap, EI): m/z (%) ) 267
(35, [M+]), 266 (15), 196 (100), 195 (32), 167 (20), 166 (22), 152
(20).
9
4832 J. AM. CHEM. SOC. VOL. 129, NO. 15, 2007

Biaryl Synthesis
A R T I C L E S
Synthesis of 2′-Methylsulfonyl-4-methylbiphenyl (7hc). Compound
7hc was prepared following Method B′ from 2-methylsulfonylbenzoic
acid (10h) (200 mg, 1.00 mmol) and 4-bromotoluene (4c) (205 mg,
1.20 mmol), yielding 7hc as a white solid (102 mg, 42%). The
spectroscopic data (NMR, GC-MS) matched those reported in the
literature for 2′-methylsulfonyl-4-methylbiphenyl [CAS: 632339-04-
9]. Compound 7hc was also prepared following Method C from
2-methylsulfonylbenzoic acid (10h) (260 mg, 1.30 mmol) and 4-bro-
motoluene (4c) (171 mg, 1.00 mmol), yielding 7hc as a white solid
(239 mg, 97%).
Synthesis of 2-Fluoro-4′-methylbiphenyl (7ic). Compound 7ic was
prepared following Method B′ from 2-fluorobenzoic acid (10i) (140
mg, 1.00 mmol) and 4-bromotoluene (4c) (205 mg, 1.20 mmol),
yielding 7ic as a colorless oil (143 mg, 76%). The spectroscopic data
(NMR, GC-MS) matched those reported in the literature for 2-fluoro-
4′-methylbiphenyl [CAS: 720937-41-5].
Synthesis of 4-Methyl-2′-methoxybiphenyl (7jc). Compound 7jc
was prepared following Method B′ from 2-methoxybenzoic acid (10j)
(152 mg, 1.00 mmol) and 4-bromotoluene (4c) (205 mg, 1.20 mmol),
yielding 7jc as a white solid (92 mg, 46%). The spectroscopic data
(NMR, GC-MS) matched those reported in the literature for 4-methyl-
2′-methoxybiphenyl [CAS: 92495-53-9].
Synthesis of 4′-Methyl-2′-(N-phenylamino)biphenyl (7kc). Com-
pound 7kc was prepared following Method C from diphenylamine-2-
carboxylic acid (10k) (276 mg, 1.30 mmol) and 4-bromotoluene (4c)
(171 mg, 1.00 mmol), yielding 7kc as a white solid (237 mg, 91%).
The spectroscopic data (NMR, GC-MS) matched those reported in the
literature for 4′-methyl-2′-(N-phenylamino)biphenyl [CAS: 911217-
14-6].
Synthesis of 4-Methyl-2′-(trifluoromethyl)biphenyl (7lc). Com-
pound 7lc was prepared following Method B′ from 2-(trifluoromethyl)-
benzoic acid (10l) (190 mg, 1.00 mmol) and 4-bromotoluene (4c) (205
mg, 1.20 mmol), yielding 7lc as a white solid (73 mg, 31%). The
spectroscopic data (NMR, GC-MS) matched those reported in the liter-
ature for 4-methyl-2′-(trifluoromethyl)biphenyl [CAS: 145486-55-1].
Synthesis of N-(4′-Methylbiphenyl-2-yl)acetamide (7mc). Com-
pound 7mc was prepared following method C from N-acetylanthranilic
acid (10 m) (232 mg, 1.30 mmol) and 4-bromotoluene (4c) (171 mg,
1.00 mmol), yielding 7mc as a white solid (94 mg, 42%). The
spectroscopic data (NMR, GC-MS) matched those reported in the
literature for N-(4′-methylbiphenyl-2-yl)acetamide [CAS: 76472-82-7].
Synthesis of 1-p-Tolylnaphthalene (7nc). Compound 7nc was
prepared following Method B′ (preformed at 150 °C) from 1-naphtoic
acid (10n) (190 mg, 1.00 mmol) and 4-bromotoluene (4c) (205 mg,
1.20 mmol), yielding 7nc as a white solid (124 mg, 57%). The
spectroscopic data (NMR, GC-MS) matched those reported in the
literature for 1-p-tolylnaphthalene [CAS: 27331-34-6].
Synthesis of 1-Methyl-4-trans-styrylbenzene (7pc). Compound 7pc
was prepared following Method B′ from trans-cinnamic acid (10p) (148
mg, 1.00 mmol) and 4-bromotoluene (4c) (205 mg, 1.20 mmol),
yielding 7pc as a white solid (157 mg, 80%). The spectroscopic data
(NMR, GC-MS) matched those reported in the literature for 1-methyl-
4-trans-styrylbenzene [CAS: 1657-45-0].
Synthesis of 4-Methyl-4′-methoxybiphenyl (7rc). Compound 7rc
was prepared following Method A (preformed at 160 °C) from
4-methoxybenzoic acid (10r) (228 mg, 1.50 mmol) and 4-bromotoluene
(4c) (171 mg, 1.00 mmol), yielding 7rc as a colorless oil (82 mg, 41%).
The spectroscopic data (NMR, GC-MS) matched those reported in the
literature for 4-methyl-4′-methoxy-biphenyl [CAS: 53040-92-9].
Synthesis of 4′-Chloro-3-methyl-2-nitrobiphenyl (7ta). Compound
7ta was prepared following Method B from 3-methyl-2-nitrobenzoic
acid (10t) (272 mg, 1.50 mmol) and 4-bromochlorobenzene (4a) (191
mg, 1.00 mmol), yielding 7ta as a yellow solid (184 mg, 74%). The
spectroscopic data (NMR, GC-MS) matched those reported in the
literature for 4′-chloro-5-methoxy-2-nitro-biphenyl [CAS: 911217-06-
6].
Synthesis of 4′-Chloro-5-methoxy-2-nitrobiphenyl (7ua). Com-
pound 7ua was prepared following Method B from 5-methoxy-2-
nitrobenzoic acid (10u) (296 mg, 1.50 mmol) and 4-bromochloroben-
zene (4a) (191 mg, 1.00 mmol), yielding 7ua as a yellow solid (204
mg, 77%). The spectroscopic data (NMR, GC-MS) matched those
reported in the literature for 4′-chloro-5-methoxy-2-nitro-biphenyl
[CAS: 911217-07-7].
Synthesis of 4′-Chloro-5-methyl-2-nitrobiphenyl (7va). Compound
7va was prepared following Method B from 5-methyl-2-nitrobenzoic
acid (10v) (271 mg, 1.50 mmol) and 4-bromochlorobenzene (4a) (191
mg, 1.00 mmol), yielding 7va as a yellow solid (126 mg, 77%). The
spectroscopic data (NMR, GC-MS) matched those reported in the
literature for 4′-chloro-5-methyl-2-nitrobiphenyl [CAS: 70690-00-5].
General Procedure for the Decarboxylation Study (Table 3). An
oven-dried vessel was charged with the carboxylic acid (10a-s) (1.00
mmol), Cu2O (10.7 mg, 0.075 mmol), phenanthroline (27.0 mg, 0.15
mmol), and the appropriate amount of potassium bromide (0, 0.15, or
1.00 mmol, see Table 3). After the vessel was flushed with alternating
vacuum and nitrogen purge cycles, a degassed solution of n-tetradecane
in a mixture of NMP (1.5 mL) and quinoline (0.5 mL) was added Via
syringe. The resulting mixture was stirred at 170 °C for 6 h. Then the
reaction mixture was allowed to cool to room temperature and was
diluted with ethyl acetate (2 mL). A sample of the reaction mixture
(0.25 mL) was dissolved in ethyl acetate (2 mL), washed with HCl (1
N, 2 mL), dried over MgSO4/NaHCO3, and analyzed by GC.
Synthesis of 2-p-Tolylthiophene (7oc). Compound 7oc was prepared
following Method B′ from thiophene-2-carboxylic acid (10o) (128 mg,
1.00 mmol) and 4-bromotoluene (4c) (205 mg, 1.20 mmol), yielding
7oc as a white solid (109 mg, 62%). The spectroscopic data (NMR,
GC-MS) matched those reported in the literature for 2-p-tolylthiophene
[CAS: 16939-04-1].
Acknowledgment. We thank Dr. N. Mu¨ller and M. Blanchot
for helpful discussions, and gratefully acknowledge the financial
support by Saltigo GmbH and the DFG.
JA068993+
9
J. AM. CHEM. SOC. VOL. 129, NO. 15, 2007 4833