Synthesis of biaryls and aryl ketones via microwave-assisted decarboxylative cross-couplings

Article abstract of DOI:10.1002/adsc.200900337

A protocol for the microwave-assisted decarboxylative cross-couplings of carboxylic acid salts with aryl halides has been developed that allows the synthesis of various biaryls and aryl ketones in high yields. After careful adaptation of the bimetallic ca

Full text of DOI:10.1002/adsc.200900337

FULL PAPERS
DOI: 10.1002/adsc.200900337
Synthesis of Biaryls and Aryl Ketones via Microwave-Assisted
Decarboxylative Cross-Couplings
Lukas J. Gooßen,a,* Bettina Zimmermann,a Christophe Linder,a Nuria Rodrꢀguez,a
Paul P. Lange,a and Jens Hartunga
a
FB Chemie – Organische Chemie, TU Kaiserslautern, Erwin-Schroedinger-Strasse, Geb. 54, 67663 Kaiserslautern,
Germany
Fax : (+49)-631-205-3921; e-mail: goossen@chemie.uni-kl.de
Received: May 14, 2009; Revised: July 22, 2009; Published online: October 22, 2009
Abstract: A protocol for the microwave-assisted de- formed within only five minutes in concentrated so-
carboxylative cross-couplings of carboxylic acid salts lution in a sealed vessel. This greatly simplified reac-
with aryl halides has been developed that allows the tion protocol is ideally suited for applications in par-
synthesis of various biaryls and aryl ketones in high allel synthesis and drug discovery.
yields. After careful adaptation of the bimetallic cat-
alyst system and reaction conditions, these mechanis- Keywords: biaryls; copper; cross-coupling; micro-
tically complex transformations can now be per- wave heating; palladium
Introduction
cross-coupled with a carbon electrophile, following
the general mechanism outlined in Scheme 2.
À
Cross-coupling reactions under formation of C C
This approach has successfully been employed in
bonds are indispensable tools in organic synthesis.[1] the synthesis of biaryls from aromatic carboxylates
In this context, decarboxylative cross-couplings have and aryl bromides,[3] chlorides,[4] and triflates,[5] as well
recently emerged as an advantageous alternative to as of aryl ketones from potassium a-oxocarboxy-
the transition metal-catalyzed cross-coupling of pre- lates.[6] Optimized reaction protocols have been devel-
formed organometallic reagents (Scheme 1).[2]
oped for both small- and large-scale applications,[7]
We have shown that organometallic species can be and the preparative value of this reaction type has
generated in situ by extrusion of CO2 from a simple been demonstrated in the synthesis of pharmaceuti-
carboxylate salt in the coordination sphere of a cally relevant substances.[8]
copper catalyst. The resulting organocopper species is
Similar decarboxylative coupling reactions have
then transmetallated to a palladium co-catalyst and also been reported by other groups. Myers et al.[9]
have introduced the concept of decarboxylative cou-
plings in their oxidative decarboxylative Heck reac-
tion. Steglich et al.[10] as well as Forgione and Bilo-
deou et al.[11] have disclosed oxidative decarboxylative
arylations of five-ring heteroarenecarboxylic acids.
Becht et al.[12] showed that particularly electron-rich
Scheme 1. Transition metal-catalyzed cross-coupling reac-
tions.
arenecarboxylates can be smoothly converted using
Pd catalysts along with silver-based mediators. Crab-
tree has recently combined the concepts of oxidative
[13]
À
decarboxylative couplings with C H activation, an
approach that was further elaborated by Glorius
et al.[14] Decarboxylative reaction variants have also
been disclosed for Sonogashira couplings,[15] C S cou-
À
plings[16] and allylation reactions.[17]
Whereas, in principle, carboxylic acids are an ap-
pealing source of carbon nucleophiles, synthetic or-
ganic chemists may still hesitate to switch from tradi-
Scheme 2. Mechanism of the decarboxylative cross-coupling. tional to decarboxylative cross-couplings, reluctant to
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Lukas J. Gooßen et al.
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submit their valuable starting materials to the pro- build-up of carbon dioxide gas on the pressure sensor.
longed thermal stress involved in current protocols, Finally, the CO2 by-product would not be able to
that is, 1608C over many hours. We saw the efficient escape and carry with it any volatile starting materials
heating provided by microwave irradiation as a prom- as is often the case at high temperatures in open stan-
ising approach to minimize reaction times in decar- dard glassware.
boxylative cross-couplings and enhance their practi-
cality.
Single-mode laboratory microwave reactors have Results and Discussion
become established as standard equipment in many
chemistry labs throughout academia and industry. In search for a suitable microwave protocol, we chose
They were found to be advantageous for many tradi- the reaction of potassium 2-nitrobenzoate (1a) with 4-
tional transition metal-catalyzed reactions,[18] e.g., tolyl bromide (2a) as a model, knowing from previous
Suzuki cross-couplings,[19] Heck reactions,[20] Buch- investigations that this substrate combination reacts
wald–Hartwig amination reactions,[21] and decarboxy- very reliably under appropriate conditions. The reac-
lative reactions of the Heck-type,[11] which can thus be tion proceeds smoothly using conventional heating at
carried out within short reaction times and in high 1608C for 24 h and a catalyst system consisting of
yields. In this context, Forgione and Bilodeau used copper iodide, 1,10-phenanthroline, and palladium
microwave radiation to promote their monometallic acetylacetonate in NMP.[2b] However, transferring the
Pd-catalyzed decarboxylative arylation of five-mem- reaction to a microwave under otherwise unchanged
bered heteroarene-2-carboxylic acids (Scheme 3).[11]
conditions led to varying and mostly unsatisfactory re-
Crabtree et al.[13] reported microwaves to be benefi- sults. The reaction mixture strongly absorbs micro-
cial in his Pd-catalyzed decarboxylative coupling of in wave radiation, causing a rapid increase in tempera-
situ-formed silver carboxylates, where Ag(I) is used in ture and pressure during the first few seconds, while
large excess as it also functions as a stoichiometric ox- the suspension is still inhomogeneous and catalyst
idant.
preformation incomplete. From the pressure graphs,
In contrast to these processes, our decarboxylative we concluded that the catalyst often lost its activity
cross-coupling protocol is based on the synchronized within a minute, presumably due to local overheating,
catalytic cycles of two different metals, and will only and that the reactions thus stalled at incomplete con-
work well if the delicate balance between them is not versions, most of the starting material was recovered
disturbed. Achieving such a balance in the microwave unchanged. The palladium catalyst proved to be par-
is not an easy task, knowing from previous investiga- ticularly sensitive, as appreciable amounts of Pd black
tions that microwave irradiation accelerates the Cu- were usually formed.
catalyzed decarboxylation step to a much larger
The decisive measures towards reproducibility were
to reduce the amount of solvent to 1 mL on a 1 mmol
extent than the cross-coupling step.[22]
We were thus not surprised that initial attempts at scale, to limit the microwave power to 50 W, and to
simply transferring the existing procedures for the homogenize the reaction mixture prior to microwave
cross-coupling, for example, of potassium 2-nitroben- irradiation by stirring it for 10 min at 508C in the
zoate with 4-tolyl bromide, to the microwave failed sealed vial. This way, an encouraging yield of 29%
(see below). Still, we were motivated to continue this was achieved after a reaction time of 10 min, at a
effort because, in theory, microwave technology per- maximum temperature set to 1608C (Table 1,
fectly meets the requirements of decarboxylative cou- entry 1). Alternatively, the catalyst can be pre-formed
plings on the laboratory scale, combining efficient directly in the microwave when limiting the power to
heating with the possibility to use small, contained 5 W and 1008C for the catalyst preformation (1 min),
vessels certified for pressure reactions. It would thus and then raising it to 15 W and 1608C until the pres-
be comparatively simple to provide the dry and inert sure buildup levels out, usually 4 min (Table 1,
conditions needed for the reactions. Moreover, their entry 2). When performing the reaction on a 1 mmol
progress would easily be followed by monitoring the scale, the pressure never reached 6 bar, which we con-
Scheme 3. Biaryl synthesis according to Bilodeau and Forgione.
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Synthesis of Biaryls and Aryl Ketones via Microwave-Assisted Decarboxylative Cross-Couplings
FULL PAPERS
sidered to be safe taking into account that the vessels even in excess of, 20 bar, which was the limit for the
used are certified for up to 20 bars.
vessels used.
Systematic investigations revealed that the yields
In order to probe whether the reduction of the re-
increased at higher temperatures (Table 1, entries 1, action time was indeed caused by the microwave irra-
3–6), causing the internal pressure to rise to a moder- diation, we conducted a control experiment in which
ate value of 6 bar at 1908C. At this temperature, the an identical reaction vessel was completely sub-
reaction time could be reduced to 5 min (Table 1, merged into a tightly fitting cavity of an aluminium
entry 7). The combination of palladium acetylaceto- block preheated to 2008C (Table 1 entries 19, 20).
nate, copper iodide, and 1,10-phenanthroline re- Even when heated in this efficient way, the reaction
mained the catalyst of choice (Table 1, entries 8–11). took 6 h to complete, demonstrating that a compara-
Whereas the amount of palladium could be reduced ble rate enhancement cannot be achieved when in-
to 1 mol%, 3 mol% of copper were required for full creasing the temperature in the conventional heating
conversion (Table 1, entries 9, 12).
protocol.
Under optimized conditions, the biaryl product 3aa
The best solvent system consisted of a mixture of
NMP and quinoline (Table 1, entry 8); either solvent was formed in high yields starting from preformed po-
individually was less effective (Table 1, entries 13, 14). tassium 2-nitrobenzoate (Table 1, entry 8). It is also
Non-polar solvents such as mesitylene did not allow possible to deprotonate 2-nitrobenzoic acid in situ
for effective heating, while lower boiling polar sol- with potassium carbonate, while trapping the reaction
vents such as THF caused pressures too close to, or water with molecular sieves. However, we found this
Table 1. Investigation of the conditions.[a]
#
T [8C]
t [min]
Catalyst
2% Pd(acac)2, 3% CuI
Solvent
Yield [%][b]
1
160
160
170
180
190
200
190
190
190
190
190
190
190
190
190
190
190
190
200
200
10
10
10
10
10
10
5
5
5
5
5
5
5
5
5
5
5
5
1 h
6 h
G
NMP/quin.
NMP/quin.
NMP/quin.
NMP/quin.
NMP/quin.
NMP/quin.
NMP/quin.
NMP/quin.
NMP/quin.
NMP/quin.
NMP/quin.
NMP/quin.
NMP
quin.
mes.
DMF
NMP/mes.
NMP/quin.
NMP/quin.
NMP/quin.
29
20
49
75
88
86
87
87
71
72
26
48
57
50
0
2[c]
3
2% Pd(acac)2, 3% CuI
2% Pd(acac)2, 3% CuI
2% Pd(acac)2, 3% CuI
2% Pd(acac)2, 3% CuI
2% Pd(acac)2, 3% CuI
2% Pd(acac)2, 3% CuI
1% Pd(acac)2, 3% CuI
1% Pd(OAc)2, 3% CuI
1% PdBr2, 3% CuI
1% Pd(dba)2, 3% CuI
1% Pd(acac)2, 1.5% CuI
1% Pd(acac)2, 3% CuI
1% Pd(acac)2, 3% CuI
1% Pd(acac)2, 3% CuI
1% Pd(acac)2, 3% CuI
1% Pd(acac)2, 3% CuI
1% Pd(acac)2, 3% CuI
1% Pd(acac)2, 3% CuI
1% Pd(acac)2, 3% CuI
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
4
5
6
7
8
9
10
11
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
E
N
T
T
ACHTUNGTRENNUNG
12[d]
13[e]
14[e]
15[e]
16[e]
17[f]
18[g]
19[h]
20[h]
49
55
55
48
87
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
[a]
Reaction conditions: 1.2 mmol potassium 2-nitrobenzoate, 1.0 mmol 4-bromotoluene, 0.03 mmol CuI, 0.05 mmol 1,10-phe-
nanthroline, 0.02 mmol Pd source, 1.0 mL of a 1:1 mixture of NMP and quinoline. All reactions were performed at a max-
imum of 50 W; quin.=quinoline, mes.=mesitylene.
Conversions were determined by GC analysis using n-tetradecane as internal standard.
Catalyst pre-formed directly in the microwave.
0.025 mmol 1,10-phenanthroline.
1.0 mL solvent.
1.0 mL of a 1:1 mixture of NMP and mesitylene.
1.2 mmol 2-nitrobenzoic acid, 1.2 mmolK2CO3, 250 mg of 3 ꢂ molecular sieves.
Reaction was carried out in an oil bath.
[b]
[c]
[d]
[e]
[f]
[g]
[h]
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Table 2. Substrate scope with regard to the aryl halides.[a]
procedure to be less convenient as the additional
amount of CO2 and water formed in the deprotona-
tion step led to a further pressure increase in the reac-
tion vessel, which we considered to be an unnecessary
potential risk to take. We also found that for most
substrates, the conversion was slightly lower using the
in-situ protocol, and that deposition of Pd black was
observed. We attributed this to local overheating at
the molecular sieves (Table 1, entry 18).
Having established a reliable protocol, we next
tested its generality by applying it to the synthesis of
biaryls from various carboxylates 1 and aryl halides 2.
As can be seen from Table 2, both electron-rich and
electron-poor aryl bromides were smoothly coupled
with potassium 2-nitrobenzoate (1a) within just five
minutes at an average power of 10–15 W, in yields
that are comparable with those achieved after 24 h of
conventional heating. Common functionalities are tol-
erated, and even a basic nitrogen heterocycle was
coupled in high yields (compound 2g).
#
1
ArX
Product
Yield [%][b]
93
3aa
2
3
4
5
6
7
3ab
3ac
3ad
3ae
3af
78
84
92
87
64
83
57
An analogous adaptation to the microwave of the
recently reported catalyst system for decarboxylative
cross-couplings of aryl chlorides was also successful,
as demonstrated in the coupling of potassium 2-nitro-
benzoate (1a) with 4-chlorotoluene (2h) in the pres-
ence of CuI/1,10-phenanthroline and PdACTHNUTRGENUG(N acac)2/di(tert-
butyl)biphenylphosphine (Table 2, entry 8).
3ag
3aa
The scope of the protocol with regard to the car-
boxylate substrates was tested in their coupling with
4-bromotoluene (2a). We were pleased to find that
the full range of arenecarboxylic acid salts that can
presently be decarboxylated with a copper/phenan-
throline system was successfully converted (Table 3):
ortho-substituted arenecarboxylates and heterocyclic
derivatives such as 2-thiophenecarboxylate reacted
smoothly in good to moderate yields.
8[c]
[a]
Reaction conditions: 1.2 mmol potassium 2-nitroben-
zoate, 1.0 mmol aryl bromide, 0.03 mmol CuI, 0.05 mmol
1,10-phenanthroline, 0.01 mmol PdACTHNUTRGEN(UNG acac)2, 0.5 mL NMP,
0.5 mL quinoline, 1908C, 50 W, 5 min.
Isolated yields.
0.5 mmol 4-chlorotoluene, 0.01 mmol di(tert-butyl)biphe-
nylphosphine as ligand.
[b]
[c]
Examples 5aa and 5ba show that the decarboxyla-
tive cross-coupling of a-oxocarboxylates with aryl
bromides under formation of aryl ketones can also be
carried out under microwave conditions with substan- boxylation step of arenecarboxylates other than 2-
tial rate acceleration (Scheme 4). substituted or heterocyclic derivatives. This limitation
As previously observed in the thermal reaction pro- can presently only be overcome under halide-free
tocol, the catalyst system is widely applicable to 2- conditions by the use of aryl triflates as carbon elec-
substituted or hetereocyclic deriviatives. It is less suit- trophiles.[5]
able for electron-rich arene carboxylates such as 2-
methoxybenzoate. Even after substantial modifica-
tions to the Pd/Cu catalyst system, only modest yields Conclusions
were obtained. For the conversion of electron-rich
substrates, we therefore recommend the use of
A convenient microwave-assisted decarboxylative
Pd/Ag-based systems, which show the best activity for cross-coupling of aryl and acyl carboxylates with aryl
precisely this substrate class and thus ideally comple- bromides has been developed. Benefitting from the
ment the substrate scope of the present protocol.
efficient heating and possibility to use small, con-
Potassium 3-nitrobenzoate (1j) represents the per- tained vessels certified for pressure reactions, the pro-
formance limit of the current catalyst system under tocol allows a fast and convenient synthesis of a
microwave conditions just as with thermal heating. broad variety of biaryls and aryl ketones. Electron-
With this copper/phenanthroline-based decarboxyla- rich and -poor aryl bromides are coupled in high
tion catalyst, halide salt byproducts impede the decar- yields within 5 min, thus making this protocol attrac-
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Synthesis of Biaryls and Aryl Ketones via Microwave-Assisted Decarboxylative Cross-Couplings
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Table 3. Substrate scope with regard to the aryl carboxylate-
tive for organic synthesis and parallel reactions in
drug discovery.
s.[a]
Experimental Section
General Methods
#
1
Carboxylate
Product
Yield [%][b]
81
All reactions were performed in oven-dried microwave vials
(10 mL) containing a Teflon-coated stir bar and a septum
under an argon atmosphere. Three freeze-pump-thaw cycles
were preformed before the reagents were mixed. All micro-
wave irradiation experiments were carried out in a mono-
mode microwave apparatus equipped with a pressure con-
trol system and a vertically-focused IR temperature sensor.
After the irradiation period, the reaction vessel was cooled
rapidly (60–120 sec) to ambient temperature by air jet cool-
ing. The maximum pressure detected during the reaction
was 5.5 bar. GC analyses were carried out using a capillary
column (phenyl methyl siloxane, 30 mꢃ320ꢃ0.25, 100/2.3–
30–300/3) and a time program beginning with 2 min at 608C
followed by 308CminÀ1 ramp to 3008C, then 3 min at this
temperature. Column chromatography was performed on
silica gel (12 g). NMR spectra were recorded at 200, 400 or
600 MHz using CDCl3, MeOH-d4, DMSO-d6 and D2O as
solvents, with proton and carbon resonances at 200/400/
600 MHz and 50/101/151 MHz, respectively. Mass spectral
data were acquired on a GC-MS instrument. Unless other-
wise noted, all materials were obtained from commercial
suppliers and used without further purification. 1-Methyl-2-
pyrrolidone (NMP) was dried by removing water as a tolu-
ene azeotrope prior to use. Quinoline was distilled over 3 ꢂ
molecular sieves prior to use. Copper salts and potassium
fluoride were dried under vacuum at 608C; potassium car-
bonate was dried under vacuum at 1208C prior to use. All
potassium salts of the carboxylic acids were dried under
vacuum at room temperature for 2 h prior to use.
3ba
2
3
3ca
3da
75
38
4[c]
5[d]
6
3ea
3fa
3ga
54
67
35
7
3ha
87
8
9
3ia
3ja
81
5[e]
10
11
3ka
31
Procedure for the Synthesis of the Potassium
Carboxylates 1a–l and the Potassium a-
Oxocarboxylates 4a and b
3la
38
0
A 250-mL, two-neck, round-bottom flask was charged with
the carboxylic acid (20.0 mmol) and ethanol (20 mL). To
this,
a
solution of potassium tert-butoxide (2.24 g,
20.0 mmol) in ethanol (20 mL) was added dropwise over
2 h. After complete addition, the reaction mixture was
stirred for another 1 h at room temperature. The gradual
formation of a white precipitate was observed. The resulting
solid was collected by filtration through a 7 cm Bꢄchner
funnel, washed sequentially with ethanol (2ꢃ10 mL) and
cold (08C) diethyl ether (10 mL), transferred to a round-
bottomed flask, and dried at 2ꢃ10À3 mmHg to provide the
corresponding potassium carboxylates 1a–l/a-oxocarboxy-
lates 4a, b in 81–98% yield.
12
3ma
[a]
Reaction conditions: 1.2 mmol potassium carboxylate,
1.0 mmol 4-bromotoluene, 0.10 mmol CuI, 0.17 mmol
1,10-phenanthroline, 0.01 mmol PdACTHNUTRGEN(UNG acac)2, 0.5 mL NMP,
0.5 mL quinoline, 1908C, 50 W, 5 min.
Isolated yields.
[b]
[c]
[d]
0.10 mmol Cu2O.
1.2 mmol 2-cyanobenzoic acid, 0.15 mmol CuO,
0.15 mmol 1,10-phenanthroline, 0.02 mmol PdBr2,
0.50 mmol KF, 1.0 mmolK2CO3, 250 mg 3 ꢂ molecular
sieves, 1.00 mL quinoline, 2508C, max. 150 W, 5 min.
GC yield.
General Procedure for the Biaryl Synthesis (Table 2/
Table 3)
[e]
Method A (Table 2): An oven-dried 10-mL microwave vial
was charged with potassium 2-nitrobenzoate (1a) (246 mg,
1.20 mmol), copper(I) iodide (5.70 mg, 0.03 mmol), palladi-
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Scheme 4. Decarboxylative cross-coupling of a-oxocarboxylates with aryl bromides.
A
4-chlorobenzene (2d) (195 mg, 1.00 mmol). Purification by
column chromatography (SiO2, hexane/ethyl acetate 4:1) af-
forded 3ad as a yellow solid; yield: 220 mg (92%).
2,4’-Dinitrobiphenyl (3ae): Compound 3ae [CAS: 606–81–
5] was prepared following Method A from potassium 2-ni-
trobenzoate (1a) (246 mg, 1.20 mmol) and 1-bromo-4-nitro-
benzene (2e) (202 mg, 1.00 mmol). Purification by column
chromatography (SiO2, hexane/ethyl acetate 4:1) afforded
3ae as an orange solid; yield: 212 mg (87%).
nanthroline (9.00 mg, 0.05 mmol). The reaction vessel was
sealed, evacuated and flushed with argon three times. Subse-
quently, a solution of the aryl bromide (2a–g) (1.00 mmol)
in NMP (0.5 mL) and quinoline (0.5 mL) was added via sy-
ringe. The resulting mixture was first stirred in a water bath
at 508C for 10 min, then irradiated in the microwave at
1908C for 5 min at a maximum power of 50 W causing the
pressure to rise to 5.5 bar, then air-jet cooled. The reaction
mixture was diluted with aqueous HCl (1N, 10 mL) and ex-
tracted with ethyl acetate (3ꢃ20 mL). The combined organic
layers were washed with water and brine, dried over
MgSO4, filtered, and the volatiles were removed under
vacuum. The residue was purified by column chromatogra-
phy (SiO2, ethyl acetate/hexane gradient), yielding the cor-
responding biaryl.
We found that this reaction can be conducted safely on
1 mmol scales using unscratched 10-mL vessels certified for
pressures of up to 20 bar, because under these conditions,
the pressure remains well below 6 bar. However, care has to
be taken when performing the reaction on scales of 3 mmol
or more. One has to remember that one equivalent of gas-
eous carbon dioxide is released within the process. The pres-
sure must be monitored carefully, as in rare cases, a palladi-
um mirror forms which may cause strong local overheating
and ultimately a bursting of the vessel.
4-Methyl-2’-nitrobiphenyl (3aa): Compound 3aa [CAS:
70680–21–6] was prepared following Method A from potas-
sium 2-nitrobenzoate (1a) (246 mg, 1.20 mmol) and 4-bro-
motoluene (2a) (171 mg, 1.00 mmol). Purification by column
chromatography (SiO2, hexane/ethyl acetate 4:1) afforded
3aa as an orange oil; yield: 198 mg (93%).
Compound 3aa was also prepared following Method A
but on 0.50 mmol scale from potassium 2-nitrobenzoate (1a)
(123 mg, 0.60 mmol) and 4-chlorotoluene (2h) (63.3 mg,
0.50 mmol). Purification by column chromatography (SiO2,
hexane/ethyl acetate 4:1) afforded 3aa as an orange oil;
yield: 61.0 mg (57%).
4-Acetyl-2’-nitrobiphenyl (3af): Compound 3af [CAS:
5730–96–1] was prepared following Method A from potassi-
um 2-nitrobenzoate (1a) (246 mg, 1.20 mmol) and 4-bromo-
AHCTUNGTREGaNNUN cetophenone (2f) (201 mg, 1.00 mmol). Purification by
column chromatography (SiO2, hexane/ethyl acetate 4:1) af-
forded 3af as a light yellow solid; yield: 157 mg (64%).
3-(2-Nitrophenyl)pyridine (3ag): Compound 3ag [CAS:
4253–80–9] was prepared following Method A from potassi-
um 2-nitrobenzoate (1a) (246 mg, 1.20 mmol) and 3-bromo-
pyridine (2g) (158 mg, 1.00 mmol). Purification by column
chromatography (SiO2, hexane/ethyl acetate 3:2) afforded
3ag as an orange oil; yield: 167 mg (83%).
Method B (Table 3): An oven-dried 10-mL microwave
vial was charged with the potassium carboxylate (1b–l)
(1.20 mmol), copper(I) iodide (19.0 mg, 0.10 mmol), palla-
dium(II) acetylacetonate (3.00 mg, 0.01 mmol) and 1,10-phe-
nanthroline (29.9 mg, 0.16 mmol). The reaction vessel was
sealed, evacuated and flushed with argon three times. Subse-
quently,
a solution of 4-bromotoluene (2a) (171 mg,
1.00 mmol) in NMP (0.5 mL) and quinoline (0.5 mL) was
added via syringe. The resulting mixture was first stirred in
a water bath at 508C for 10 min, then irradiated in the mi-
crowave at 1908C for 5 min at a maximum power of 50 W,
then air-jet cooled. The reaction mixture was diluted with
aqueous HCl (1N, 10 mL) and extracted with ethyl acetate
(3ꢃ 20 mL). The combined organic layers were washed with
water and brine, dried over MgSO4, filtered, and the vola-
tiles were removed under vacuum. The residue was purified
by column chromatography (SiO2, ethyl acetate/hexane gra-
dient), yielding the corresponding biaryl.
2-Fluoro-4’-methylbiphenyl (3ba): Compound 3ba [CAS:
72093–41–5] was prepared following Method B from potassi-
um 2-fluorobenzoate (1b) (214 mg, 1.20 mmol) and 4-bro-
motoluene (2a) (171 mg, 1.00 mmol). Purification by column
chromatography (SiO2, hexane) afforded 3ba as a colorless
oil; yield: 151 mg (81%).
4-Methoxy-2’-nitrobiphenyl (3ab): Compound 3ab [CAS:
20013–55–2] was prepared following Method A from potas-
sium 2-nitrobenzoate (1a) (246 mg, 1.20 mmol) and 4-bro-
moanisole (2b) (191 mg, 1.00 mmol). Purification by column
chromatography (SiO2, hexane/ethyl acetate 4:1) afforded
3ab as a yellow solid; yield: 192 mg (78%).
1-(2-Nitrophenyl)naphthalene (3ac): Compound 3ac
[CAS: 5415–59–8] was prepared following Method A from
potassium 2-nitrobenzoate (1a) (246 mg, 1.20 mmol) and 1-
bromonaphthalene (2c) (222 mg, 1.00 mmol). Purification by
column chromatography (SiO2, hexane/ethyl acetate 4:1) af-
forded 3ac as an orange solid; yield: 222 mg (84%).
2-(4-Methylphenyl)thiophene (3ca): Compound 3ca
[CAS: 16939–04–1] was prepared following Method B from
potassium thiophene-2-carboxylate (1c) (199 mg, 1.20 mmol)
and 4-bromotoluene (2a) (171 mg, 1.00 mmol). Purification
by column chromatography (SiO2, hexane) afforded 3ca as a
white solid; yield: 130 mg (75%).
4-Chloro-2’-nitrobiphenyl (3ad): Compound 3ad [CAS:
6271–80–3] was prepared following Method A from potassi-
um 2-nitrobenzoate (1a) (246 mg, 1.20 mmol) and 1-bromo-
2-(4-Methylphenyl)furan (3da): Compound 3da [CAS:
17113–32–5] was prepared following Method B from potassi-
2672
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Synthesis of Biaryls and Aryl Ketones via Microwave-Assisted Decarboxylative Cross-Couplings
FULL PAPERS
um furan-3-carboxylate (1d) (180 mg, 1.20 mmol) and 4-bro-
motoluene (2a) (171 mg, 1.00 mmol). Purification by column
chromatography (SiO2, hexane) afforded 3da as a colorless
oil; yield: 102 mg (38%).
4’-Methylbiphenyl-2-carboxylic acid isopropyl ester (3ea):
Compound 3ea [CAS: 937166–54–6] was prepared following
Method B from potassium 2-isopropyloxycarbonyl benzoate
(1e) (296 mg, 1.20 mmol), copper(I) oxide (14.3 mg,
0.10 mmol) and 4-bromotoluene (2a) (171 mg, 1.00 mmol).
Purification by column chromatography (SiO2, hexane/ethyl
acetate 4:1) afforded 3ea as a white solid; yield: 138 mg
(54%).
2-Cyano-4’-methylbiphenyl (3fa): Compound 3fa [CAS:
114772–53–1] was prepared from 2-cyanobenzoic acid (1f)
(177 mg, 1.20 mmol), copper(II) oxide (11.9 mg, 0.15 mmol),
palladium(II) bromide (5.30 mg, 0.02 mmol), 1,10-phenan-
throline (27.0 mg, 0.15 mmol), potassium carbonate (138 mg,
1.00 mmol), potassium fluoride (29.0 mg, 0.50 mmol) and
3 ꢂ molecular sieves (250 mg, pulverized and dried in the
microwave). The reaction vessel was evacuated and flushed
with argon three times. Subsequently, a solution of 4-bromo-
toluene (2a) (171 mg, 1.00 mmol) in quinoline (1.0 mL) was
added via syringe. The resulting mixture was stirred in the
microwave at 2508C for 5 min at 150 W, then diluted with
aqueous HCl (1N, 10 mL), and extracted repeatedly with
ethyl acetate (3ꢃ20 mL). The combined organic layers were
washed with water and brine, dried over MgSO4, filtered,
and the volatiles were removed under vacuum. The residue
was purified by column chromatography (SiO2, hexane/ethyl
acetate 4:1), affording 3fa as a yellow solid; yield: 130 mg
(68%).
toluene (2a) (171 mg, 1.00 mmol), afforded 3ja in 5% GC
yield.
1-(4-Methylphenyl)naphthalene (3ka): Compound 3ka
[CAS: 27331–34–6] was prepared following Method B from
potassium 1-naphthoate (1k) (252 mg, 1.20 mmol) and 4-bro-
motoluene (2a) (171 mg, 1.00 mmol). Purification by column
chromatography (SiO2, hexane) afforded 3ka as a colorless
solid; yield: 65.9 mg (31%).
2-Acetyl-4’-methylbiphenyl (3la): Compound 3la [CAS:
16927–79–0] was prepared following Method B from potassi-
um 2-acetylbenzoate (1l) (243 mg, 1.20 mmol) and 4-bromo-
toluene (2a) (171 mg, 1.00 mmol). Purification by column
chromatography (SiO2, hexane/ethyl acetate 4:1) afforded
3la as a yellow oil; yield: 80.5 mg (38%).
4-Methylbenzophenone (5aa): Compound 5aa [CAS: 134–
84–9] was prepared following Method B from potassium
oxophenyl acetate (4a) (226 mg, 1.20 mmol) and 4-bromoto-
luene (2a) (171 mg, 1.00 mmol). Purification by column
chromatography (SiO2, hexane/ethyl acetate 4:1) afforded
5aa as a yellow solid; yield: 162 mg (83%).
4,4’-Dimethylbenzophenone (5ba): Compound 5ba [CAS:
611–97–2] was prepared following Method B from potassi-
um oxo(4-methylphenyl) acetate (4b) (243 mg, 1.20 mmol)
and 4-bromotoluene (2a) (171 mg, 1.00 mmol). Purification
by column chromatography (SiO2, hexane/ethyl acetate 4:1)
afforded 5ba as a light yellow solid; yield: 139 mg (66%).
The spectroscopic data (1 H, 13C NMR, GC-MS) of all
known compounds were found to be identical with those re-
ported in the literature.
4-Methyl-2’-formylbiphenyl (3ga): Compound 3ga [CAS:
16191–28–9] was prepared following Method B from potassi-
um 2-formylbenzoate (1g) (226 mg, 1.20 mmol) and 4-bro-
motoluene (2a) (171 mg, 1.00 mmol). Purification by column
chromatography (SiO2, hexane/ethyl acetate 4:1) afforded
3ga as a light yellow oil; yield: 68.0 mg (35%).
Acknowledgements
We thank Saltigo GmbH, the Deutsche Forschungsgemein-
schaft, and NanoKat for funding, Umicore AG for the gener-
ous donation of catalysts and the Alexander von Humboldt
Foundation for a scholarship to N.R.
3,4’-Dimethyl-2-nitrobiphenyl (3ha): Compound 3ha was
prepared following Method B from potassium 3-methyl-2-ni-
trobenzoate (1h) (263 mg, 1.20 mmol) and 4-bromotoluene
(2a) (171 mg, 1.00 mmol). Purification by column chroma-
tography (SiO2, hexane/ethyl acetate 4:1) afforded 3ha as a
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yellow solid; yield: 198 mg (87%); mp 71–728C; H NMR
(CDCl3, 600 MHz): d =7.40 (t, J=7.7 Hz, 1H), 7.25–7.28
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13C NMR (CDCl3, 151 MHz): d =150.8 (s), 138.2 (s), 134.2
(s), 133.7 (s), 132.9 (s), 132.7 (s), 129.9 (s), 129.9 (s), 129.5
(s), 129.4 (s), 128.5 (s), 127.7 (s), 124.5 (s), 21.1 (s), 17.3 (s);
MS (EI): m/z (%)=227 (85) [M+], 210 (100), 199 (53), 182
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ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 2667 – 2674