Selective copper- or silver-catalyzed decarboxylative deuteration of aromatic carboxylic acids

Article abstract of DOI:10.1055/s-0031-1289638

The practical utility of decarboxylative transformations in organic synthesis is discussed, and the decarboxylative deuteration of (hetero)aromatic carboxylic acids is disclosed as a further example. Various monodeuterated arenes were synthesized under mild conditions, in a single step from easily accessible aromatic carboxylic acids and deuterium oxide. Copper catalysts were found to have the widest scope, but silver catalysts are superior for some ortho-substituted benzoates. A few substrates, e.g. quinoline-2-carboxylic acid, decarboxylate even in the absence of a metal catalyst. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1289638

184
FEATURE ARTICLE
Selective Copper- or Silver-Catalyzed Decarboxylative Deuteration of
Aromatic Carboxylic Acids
C
opper- or Silver-Cata
a
lyzed Deca
r
rboxyla
t
t
ive
D
e
i
n
n
of
A
romatic Carb
R
oxylic Acids udzki, Ana Alcalde-Aragonés, Wojciech I. Dzik, Nuria Rodríguez, Lukas J. Gooßen*
Department of Chemistry, Organic Chemistry, Technische Universität Kaiserslautern, Erwin-Schrödinger-Straße, 67663 Kaiserslautern,
Germany
Fax +49(631)2053921; E-mail: goossen@chemie.uni-kl.de
Received 10 October 2011; revised 14 November 2011
expensive and broadly available carboxylate salts instead
Abstract: The practical utility of decarboxylative transformations
of costly and air-sensitive pre-formed organometallic re-
agents.
in organic synthesis is discussed, and the decarboxylative deutera-
tion of (hetero)aromatic carboxylic acids is disclosed as a further
example. Various monodeuterated arenes were synthesized under
The protodecarboxylation of aromatic carboxylic acids, in
mild conditions, in a single step from easily accessible aromatic car-
which the carboxylate group is replaced by a hydrogen at-
boxylic acids and deuterium oxide. Copper catalysts were found to
om, represents the simplest decarboxylative transforma-
have the widest scope, but silver catalysts are superior for some
tion.12 This reaction is of substantial interest as a simple
ortho-substituted benzoates. A few substrates, e.g. quinoline-2-car-
model for investigating specific aspects of complex decar-
boxylative coupling reactions. Besides, it is synthetically
useful in removing surplus carboxylate groups that may
be remnants from a chosen synthetic route,13 e.g. the syn-
thesis of indoles via the Reissert reaction14 or the synthesis
of pyridines via the Hantzsch reaction.15 Miura and Satoh
employed this approach to remove carboxylate groups af-
ter using them as directing groups in a C–H functionaliza-
tion step.16 Recently, a method for the synthesis of meta-
substituted biaryls by direct ortho-arylation of benzoates,
followed by in situ removal of the directing carboxylate
group, was disclosed by Larrosa et al.17
boxylic acid, decarboxylate even in the absence of a metal catalyst.
Key words: arenes, carboxylic acids, catalysis, decarboxylation,
deuteration
In recent years, carboxylic acids have been rediscovered
as an advantageous substrate class for transition-metal-
catalyzed transformations.1 Decarboxylative couplings, in
particular, have attracted substantial attention. In 2002,
Myers reported a Heck-type reaction as the first example
of an oxidative decarboxylative coupling in which carbon
electrophiles are generated from aromatic carboxylates.2
In 2006, inspired by pioneering observations by Nilsson et
al.,3 we disclosed a redox-neutral decarboxylative cou-
pling in which carbon nucleophiles are generated in situ
from metal arenecarboxylates via extrusion of carbon di-
oxide (CO2).4 A related concept was utilized by Steglich5
and also Forgione and Bilodeau et al.6 for the arylation of
heteroarenes.
proto-
cross-couplings
and allylations
(redox-neutral)
decarboxylations
R1–H
R1–R2
carbon nucleophiles
generated from
carboxylic acids
H+
R2–X
R1
δ−
R2
O
X
Since then, catalytic decarboxylative couplings have rap-
idly developed into a generally applicable synthetic strat-
egy for C–C and C–heteroatom bond formation.7 In the
redox-neutral reaction variants, carbon nucleophiles are
generated via the extrusion of CO2 and are directly cou-
pled with an electrophilic partner. Examples are the re-
gioselective synthesis of biaryls from aromatic or
heteroaromatic carboxylates and aryl electrophiles,4,8 or
the analogous synthesis of aryl ketones or azomethines
from a-oxocarboxylates.9 In the oxidative reaction vari-
ant, carboxylic acids undergo decarboxylation and are ox-
idatively coupled with carbon- or heteroatom-based
nucleophiles10 or olefins (Scheme 1).2,11
R1
cat.
cat.
HX
addition reactions
R2
R1
O
CO2
oxidative
couplings
[O]
cat.
OH
δ+
R1
O
H–Nu
R1–Nu
cat.
R1
C–heteroatom
bond formation
Ar–H
carbon electrophiles
generated from
carboxylic acids
R2
R1–Ar
R1
couplings under
C–H activation
R2
Heck-type
reactions
Decarboxylative couplings are regiospecific because the
new bond is formed at a position predefined by the car-
boxylate group. Their key advantages lie in the use of in-
Scheme 1 Overview of decarboxylative coupling reactions
Few carboxylic acids, e.g. b-oxocarboxylic acids, are
known to readily decarboxylate in the absence of a metal
catalyst or mediator.18 The extrusion of CO2 from the ma-
SYNTHESIS 2012, 44, 184–193
Advanced online publication: 05.12.2011
DOI: 10.1055/s-0031-1289638; Art ID: T96611SS
x
x
.x
x
.2
0
1
1
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Biographical Sketches
Copper- or Silver-Catalyzed Decarboxylative Deuteration of Aromatic Carboxylic Acids
185
Martin Rudzki was born in diploma thesis covered the was funded by the Deutsche
Piekary Śląskie (Poland). field of decarboxylations, Bundesstiftung Umwelt.
He studied chemistry at the especially protodecarboxy- Currently he is a project
TU Kaiserslautern (Germa- lation of heteroaromatic car- manager at SGS Institut
ny), which included an in- boxylic
ternship at Merck KGaA in decarboxylative
acids
and Fresenius GmbH in Tau-
deutera- nusstein (Germany).
Darmstadt, and was award- tion. His graduate research
ed a Wiley-VCH prize. His in the group of L. J. Gooßen
Ana Alcalde was born in In 2010, she was a visiting of Barcelona. Her research
Pamplona (Spain) in 1983. researcher in the Gooßen interests include catalyst
She received her diploma in group. Since June 2011, she design and novel catalytic
2006 from the University of has worked at the Catalo- materials, reactions in
Valencia, where she went nian Ambient Intelligence supercritical fluids, and en-
on to pursue doctoral re- and Accessibility Center at vironmentally benign chem-
search in organic chemistry. the Autonomous University ical processes.
Wojciech I. Dzik was born ducted doctoral research un- Humboldt postdoctoral fel-
in 1982 in Columbus, OH der the guidance of B. de low in the group of L. J.
(USA). He studied Chemis- Bruin and J. N. H. Reek at Gooßen at the TU Kaiser-
try at the University of War- the University of Amster- slautern (Germany), and
saw (Poland), where he was dam (Netherlands), and works on the development
awarded an M.Sc. degree in completed his Ph.D. in of new decarboxylative cou-
2006. Subsequently, he con- 2011. Currently, he is a pling reactions.
Nuria Rodríguez was born with L. J. Gooßen as a Hum- the University of Madrid
in 1978 in Valencia (Spain). boldt postdoctoral fellow (Spain). Her current re-
After completion of her starting 2006. The emphasis search focuses on the devel-
chemistry studies at the of her work was the devel- opment of catalytic systems
University of Valencia, she opment of decarboxylative for the activation of inert C–
gained her doctorate in the cross-coupling reactions. In H bonds.
group of G. Asensio and M. 2011, she took up a Ramon
Medio-Simón. She worked y Cajal research position at
Lukas J. Gooßen graduat- in 1997, supervised by W. took up a position at the
ed in chemistry from the A. Herrmann. After a post- RWTH Aachen and in 2005,
University of Bielefeld, doctoral stay with K. B. became Professor of Organ-
with research stays in Sharpless and a position as ic Chemistry at the TU Kai-
Michigan with A. Ashe III, laboratory head at Bayer, he serslautern. His current
and Berkeley with K. P. C. gained his habilitation with research focuses on the de-
Vollhardt. He received his M. T. Reetz at the MPI für velopment of sustainable
doctorate at the TU Munich Kohlenforschung. He then catalytic transformations.
© Thieme Stuttgart · New York
Synthesis 2012, 44, 184–193

186
M. Rudzki et al.
FEATURE ARTICLE
jority of aromatic carboxylic acids needs to be promoted carbonate in N-methyl-2-pyrrolidinone, allows for the
by aqueous acid19 or by more effective transition-metal protodecarboxylation of a broad scope of ortho-substitut-
mediators, such as copper,3,20 silver,21 or mercury salts.22 ed benzoic acids (Scheme 3, results a).27b
In early work, stoichiometric amounts of metal salt and
Larrosa et al. independently developed a silver carbonate/
high temperatures were used in the protodecarboxylation
dimethyl sulfoxide catalyst system with a comparable
of aromatic carboxylic acids. For instance, halogenated
substrate scope (Scheme 3, results b).28a They further
furancarboxylic acids were protodecarboxylated by
demonstrated that in combination with 5 mol% acetic
Shepard et al. using copper metal or copper salts at tem-
acid, their catalyst system also allows the decarboxylation
peratures between 210 °C and 300 °C.20a Nilsson,3,20b
of various heteroaromatic carboxylic acids.28b
Sheppard,20c and Cohen20d improved this method by com-
bining copper with bipyridine ligands and/or aromatic
O
OH
H
amine solvents. With this protocol, activated aromatic and
vinylic carboxylic acids can also be converted into the
corresponding protonated substrates. Only few highly ac-
tivated carboxylic acids were successfully protodecarbox-
ylated when using catalytic amounts of copper
sources.23,24
[Ag] (10 mol%)
R
R
solvent, 120 °C, 16 h
H
H
H
H
Cl
NO2
MeO
OMe
Cl
Cl
Recent years have brought about significant improve-
ments in this field, and effective copper- and silver-based
catalyst systems capable of protodecarboxylating a broad
range of carboxylic acids have been disclosed. New cata-
lysts based on copper/4,7-diphenyl-1,10-phenanthroline
complexes were shown to promote effectively the decar-
boxylation of various carboxylic acids (Scheme 2).25 The
reaction conditions [Cu2O (5 mol%), 4,7-diphenyl-1,10-
phenanthroline (10 mol%), NMP–quinoline, 170 °C] tol-
erate a number of functionalities, e.g. methoxy, nitro, or
cyano groups. This protocol was further improved by us-
ing modern microwave technology, which allows reduc-
tion of the reaction time from several hours to a few
minutes, even when using a simple 1,10-phenanthroline
ligand.26
O2N
(a) 85%
(a) 92%
(b) 91%
(a) 78%
(b) 96%
(a) 87%
(b) 91%
(b) 90%
H
H
H
Br
NO2
SO2Me
MeO
MeO
OMe
(a) 90%
(a) 95%
(a) 88%
Scheme 3 Examples of silver-catalyzed protodecarboxylations by
(a) Gooßen et al.27b and (b) Larrosa et al.28a
Rhodium-catalyzed protodecarboxylations proceed at
relatively low temperatures;29 the catalyst system is gen-
erated from [(cod)Rh(OH)]2 and 1,3-bis(diphenylphos-
phino)propane. It promotes the protodecarboxylation of a
small range of ortho,ortho-disubstituted benzoic or other-
wise activated carboxylic acids already at 110 °C in a sol-
vent mixture of toluene and aqueous sodium hydroxide.
O
OH
Cu2O (5 mol%)
4,7-diphenyl-1,10-phenanthroline
(10 mol%)
H
R
R
NMP/quinoline (3:1), 170 °C
H
H
H
NO2
H
Kozlowski et al. reported that a catalyst system consisting
of 20 mol% palladium(II) trifluoroacetate in dimethyl sul-
foxide–N,N-dimethylformamide (1:20) allows the proto-
decarboxylation of electron-rich, 2,6-disubstituted
benzoic acids at the remarkably low temperature of 70
°C.30 Excess trifluoroacetic acid is added to increase the
rate of protodemetalation, which is too slow otherwise.
The stability of the intermediate aryl–metal species is
even more pronounced when starting from gold carboxy-
lates, which readily extrude CO2 but do not undergo prot-
onolysis.31
NO2
N
MeO
87%
90%
H
82%
H
SO2Me
CN
83%
60%
Scheme 2 Examples of copper-catalyzed protodecarboxylations by
Gooßen et al.27b
While decarboxylations of aliphatic carboxylic acids are
believed to follow a radical pathway,32 the mechanism of
the copper-mediated protodecarboxylation of aromatic
carboxylic acids was shown to proceed via aryl–metal in-
termediates.33 The reaction mechanisms of both copper-
and silver-catalyzed protodecarboxylations of aromatic
carboxylic acids were elucidated by DFT calculations,
The copper-based catalysts are particularly suited for me-
ta- and para-substituted benzoic acids. In contrast, silver-
based catalyst systems are highly effective for several
ortho-substituted or heterocyclic derivatives, which give
low or no yields with copper.27,28 Our recently developed
catalyst system, consisting of silver acetate and potassium
Synthesis 2012, 44, 184–193
© Thieme Stuttgart · New York

FEATURE ARTICLE
Copper- or Silver-Catalyzed Decarboxylative Deuteration of Aromatic Carboxylic Acids
187
quires rather harsh conditions and leads to the formation
of perdeuterated compounds.42 Several aliphatic acids
were decarboxylated photochemically, with selective for-
mation of monodeuterated compounds.43 A regioselective
synthesis of monodeuterated arenes is even harder to ac-
complish. Morita et al. reported that monodeuterated ben-
zene is formed when heating calcium benzoate and
calcium deuteroxide to 300 °C.44 Erlenmeyer et al. dem-
onstrated that the decarboxylative deuteration of mellitic
acid [C6(COOH)6)] leads to the formation of benzene-
d6.45 This concept was also employed by Zoltewicz et al.
to synthesize deuterated pyridine derivatives.46
O
CO2
OH
H
[M]
R
R
protonolysis
#
O
[M]
R
O
R
O
O
[M]
O
OH
[M]+ X–
+
– HX
R
R
Scheme 4 Mechanism of the copper- and silver-catalyzed protode-
carboxylation of aromatic carboxylic acids
We believed that the synthesis of monodeuterated arenes
might be possible under much milder conditions using the
new decarboxylation catalysts that we developed in the
course of our work on decarboxylative couplings.25–27
These copper- or silver-based catalysts effectively medi-
ate the extrusion of CO2 from aromatic carboxylates with
regioselective formation of an aryl–metal bond in the
ipso-position. If the subsequent protonolysis is performed
with deuterons rather than protons, monodeuterated com-
pounds should be obtained.
which correctly predicted the observed reactivity se-
quence for benzoic acids (Scheme 4).25,27
Building on the above studies of catalytic protodecarbox-
ylations, we herein present an efficient route to monodeu-
terated aromatic compounds via the extrusion of CO2
from O-deuterated aromatic carboxylates.
Deuterium-labeled compounds are of interest in several
fields of chemistry, including investigations of reaction
mechanisms, drug metabolism, kinetic studies or molecu-
lar structure analysis. The classic approach to deuterate
molecules regioselectively is to reduce functional groups
with deuteride sources such as LiAlD4,34 NaBD4,35 or
Bu3SnD (Scheme 5, right).36 The deuterolysis of organo-
metallic compounds with D2O also leads to the formation
of the corresponding deuterated compounds (Scheme 5,
top).37 Other popular deuteration methods include H–D
exchange reactions catalyzed by acid,38 base,39 and transi-
tion-metal catalysts,40 and the addition of D2 across dou-
ble bonds (Scheme 5, left).41
In order to apply the concept of decarboxylative deutera-
tion to the broadest possible range of substrates, we inves-
tigated several complementary protodecarboxylation
catalysts in analogous deuterodecarboxylation reactions.
Judging from comparative protodecarboxylation stud-
ies,27b one would expect copper systems to be the catalysts
of choice for non-ortho-substituted arenes, while silver
catalysts should be optimal for some ortho-halo-substitut-
ed benzoic acids. However, especially for some heteroar-
omatic substrates, it was not clear which catalyst system
would be the most effective. We thus comparatively stud-
ied copper- and silver-based catalysts in the protodecar-
boxylation of several heteroaromatic carboxylic acids
1a–d (Table 1).
The extrusion of CO2 from O-deuterated aromatic carbox-
ylates represents a promising approach for the regiospe-
cific introduction of a single deuteron (Scheme 5,
bottom). To date, there are only a few reports of the syn-
thesis of deuterium-labeled compounds by the decarbox-
ylation of carboxylic acids. Matsubara et al. reported a
decarboxylative deuteration of aliphatic carboxylic acids
under hydrothermal conditions. However, this method re-
For the protodecarboxylation of 1H-indole-2-carboxylic
acid (1a), the copper catalyst [Cu2O, 1,10-phenanthroline,
NMP–quinoline (3:1), 170 °C] gave better results than sil-
ver (AgOAc, NMP, 120 °C). For benzothiophene-2-car-
boxylic acid (1b), the silver catalyst proved to be more
effective than copper.
R
D
LiAlD4
D
D
HCl–D2O
R
D
D
R
OH
X = H
X = COOEt
X = MgCl
D2O
NaOD
X = H
R
D
D
Ph
OH
NaBD4
R
X
R = alkyl, aryl
R
X = COPh
[Pt], D2
D
D
R
X =
X = COOH
D2O
– CO2
[Pd], H2,
D2O
D
D
D
H
Bu3SnD
R
D
R
OH
D
X = CHO
X =
R
D
D
D
O
O
Scheme 5 Synthetic entries to deuterium-labeled compounds
© Thieme Stuttgart · New York
Synthesis 2012, 44, 184–193

188
M. Rudzki et al.
FEATURE ARTICLE
Table 1 Protodecarboxylation of Heteroaromatic Carboxylic Acidsa
this method to the deuterodecarboxylation of 2-nitroben-
zoic acid (1e) as a test substrate. Indeed, the desired ni-
trobenzene-2-d (3e) was formed in 72% yield and an
excellent 99% degree of deuteration (Table 2, entry 1).
Encouraged by this result, we applied the same method to
other benzoic acids including 2-(methylsulfonyl)benzoic
acid (1f), 2-benzoylbenzoic acid (1g), 2-(phenylami-
no)benzoic acid (1h), 4-cyanobenzoic acid (1i), and
benzothiophene-2-carboxylic acid (1b). The deuterode-
carboxylation proceeded with high regioselectivity and
method A–C
HetAr COOH
HetAr
H
Δ, 16 h
1a–d
2a–d
HetAr-COOH
Catalyst
Method
Yieldb (%)
O
Cu
Ag
–
A
B
C
98
22
0
N
H
OH
1a
O
Cu
Ag
–
A
B
C
64
79
0
Table 2 Copper-Catalyzed Decarboxylative Deuteration of Aro-
matic Carboxylic Acids (Method A¢)a
S
OH
Cu2O (5 mol%), 1,10-phenanthroline (10 mol%)
1b
Ar COOH
Ar
D
O
Cu
Ag
–
Ac
B
C
55
11
57
NMP/quinoline (3:1), D2O
170 °C, 16 h
N
1a,b,e–i
3a,b,e–i
OH
Entry Ar-COOH
Ar-D
DGb Yield
1c
(%)
(%)
O
OH
N
Cu
Ag
–
Ac
B
C
84
59
98
O
OH
D
NO2
NO2
1
2
3
4
99
72
1d
3e
1e
O
a The reactions were performed on 1-mmol scale; Method A: Cu2O (5
mol%), 1,10-phenanthroline (10 mol%), NMP–quinoline (3:1, 2 mL),
170 °C, 16 h. Method B: AgOAc (10 mol%), NMP (2 mL), 120 °C,
16 h. Method C: NMP (2 mL), 170 °C, 16 h.
OH
O
D
O
O
O
S
Me
S
77
80
50
50
77
64
Me
b The yields were determined by GC using tetradecane as internal
standard.
3f
1f
O
c Without quinoline.
OH
D
D
O
O
For six-membered nitrogen heterocycles with carboxylate
groups directly adjacent to the ring nitrogen atom, the
thermal protodecarboxylation was found to be more effec-
tive than the analogous reaction in the presence of either
metal catalyst. Thus, quinoline-2-carboxylic acid (1c) and
isoquinoline-1-carboxylic acid (1d) smoothly deuterode-
carboxylated at 170 °C. These observations indicate that
in the case of 1a and 1b, the decarboxylation involves an
aryl–metal species, whereas quinolinecarboxylic acids 1c
and 1d decarboxylate via a different mechanism.
3g
1g
O
OH
H
N
H
N
3h
1h
NC
1i
O
5
6
40
67
58c
68
NC
D
This study in combination with preceding work allowed
us to decide on the optimal method to use for the protode-
carboxylation of each class of aromatic carboxylate 1.
OH
3i
O
We next embarked on the development of deuterium ana-
logues of copper-, silver-, and non-catalyzed protodecar-
boxylation protocols. The principal challenge was to find
convenient processes for effectively replacing all protons
in the reaction medium with deuterons. For the copper-
catalyzed reactions, it proved to be most practical to add
an excess of D2O in three portions into the N-methylpyr-
rolidin-2-one–quinoline solution of the carboxylic acid
and copper oxide/1,10-phenanthroline catalyst while stir-
ring the mixture at 110 °C. The remaining gaseous D2O
and the HDO formed in the process were removed in a
continuous flow of nitrogen gas. The resulting reaction
mixture was stirred at 170 °C for 16 hours. We applied
D
S
S
OH
3b
1b
O
D
7
55:45d 54d
N
H
N
OH
H
3a/3a¢
1a
a Reaction conditions: 1 (1 mmol), Cu2O (5 mol%), 1,10-phenanthro-
line (10 mol%), NMP–quinoline (3:1, 2 mL), D2O, 16 h, 170 °C.
b DG = deuteration grade, calculated by integration of the 1H NMR
signals.
c With 4,7-diphenyl-1,10-phenanthroline.
d A mixture of 3a (deuteration at C2) and 3a¢ (deuteration at C3)
55:45.
Synthesis 2012, 44, 184–193
© Thieme Stuttgart · New York

FEATURE ARTICLE
Copper- or Silver-Catalyzed Decarboxylative Deuteration of Aromatic Carboxylic Acids
189
the corresponding monodeuterated products were ob- acid, the resulting solution was then stirred for a few min-
tained in moderate to good yields and deuteration grades. utes at 100 °C and the excess HDO and D2O were re-
A remarkable exception is 1H-indole-2-carboxylic acid moved in vacuo. After three such cycles, the resulting
(1c), where substantial scrambling of the deuterium was deuterated carboxylic acid was dissolved in NMP, added
observed, leading to the formation of a 55:45 mixture of to a reaction vial containing silver(I) acetate, and the mix-
ipso- and ortho-monodeuterated indole 3a and 3a¢. This ture was stirred at 120 °C for 16 hours.
result implies that for this specific substrate class, copper
can easily move between the C2 and the C3 position,
which provides an explanation for the lack of regiospeci-
This method allows the conversion of ortho-substituted
benzoic acids such as 5-methoxy-2-nitrobenzoic acid (1j),
2,6-dimethoxybenzoic acid (1k), 2,4,6-trichlorobenzoic
acid (1l), and 2-bromo-4,5-dimethoxybenzoic acid (1m)
ficity that we had observed when trying to apply our de-
carboxylative arylation reaction to indoles.47
Table 3 Silver-Catalyzed Decarboxylative Deuteration of Aromatic
We next tested whether the catalyst-free H/D exchange
protocol (NMP, 170 °C) that had been most effective for
the protodecarboxylation of quinoline- 1c and isoquino-
linecarboxylic acids 1d could also be used for the analo-
gous deuteration. Indeed, when a solution of the acid 1c or
1d in N-methyl-2-pyrrolidinone was subjected to proton–
deuteron exchange as described above and subsequently
heated to 170 °C for 16 hours, the desired monodeuterated
quinoline 3c and isoquinoline 3d were formed in excellent
yields and deuteration grades (Scheme 6).
Carboxylic Acids (Method B¢)a
AgOAc (10 mol%), K2CO3 (15 mol%)
Ar COOH
Ar
D
NMP, 120 °C, 16 h
1b,f,j–m
3b,f,j–m
Entry Ar-COOH
Ar-D
DGb Yield
(%)
(%)
O
OH
OH
D
NO2
NO2
1
99
97
O
MeO
MeO
1j
N
N
D
3j
D2O
OH
87%
O
99% D
D
NMP, 170 °C
16 h
MeO
OMe
MeO
OMe
1c
3c
2
99
72
77
71
O
OH
N
D
3k
1k
D2O
N
88%
99% D
O
OH
D
NMP, 170 °C
16 h
Cl
Cl
Cl
Cl
1d
3d
3
4
Scheme 6 Catalyst-free decarboxylative deuteration (method C¢) of
quinoline-2-carboxylic acid (1c) and isoquinoline-1-carboxylic acid
(1d)
Cl
Cl
3l
1l
O
OH
D
It is remarkable that the deuteration grades drop signifi-
cantly in several cases although we were confident that we
had completely exchanged all acidic protons in the reac-
tion medium with deuterons. It appears that for these sub-
strates, the N-methylpyrrolidin-2-one solvent, although its
pKa is as high as 37,48 serves as a proton source in this side
reaction. A similar process may account for protodecar-
boxylations observed as side reactions in decarboxylative
cross-couplings under rigorously anhydrous conditions.49
Br
Br
99
75
MeO
MeO
OMe
O
OMe
3m
1m
O
OH
O
D
O
O
S
S
D
5
6
65:33c 94
93:15d 61
Me
H
H
Finally, we investigated the silver-catalyzed deuterode-
carboxylation of ortho-methoxy- and halo-substituted
benzoic acids 1j–m. The protocol had to be especially
adapted to account for the particular volatility of the deu-
terated products derived from these substrates. Because
the silver-catalyzed decarboxylation starts already at 110
°C, it takes place to a significant extent before all protons
in the reaction medium are exchanged for deuterons, re-
sulting in low deuteration grades and partial evaporation
of the desired products. Therefore, the proton–deuteron
exchange needed to be complete prior to catalyst addition.
Thus, D2O was added portionwise to the solid carboxylic
3f/3f¢
1f
OH
O
D
S
S
3b/3b¢
1b
a Reaction conditions: 1 (1 mmol), AgOAc (10 mol%), K2CO3
(15 mol%), D2O, NMP (2 mL), 16 h, 120 °C.
b DG = deuteration grade, calculated by integration of the 1H NMR
signals.
c 1H and 2D NMR show 65% deuteration at the phenyl ring and 33%
deuteration at the methyl group.
d 1H and 2D NMR show 93% deuteration at C2 and 15% deuteration
at C3.
© Thieme Stuttgart · New York
Synthesis 2012, 44, 184–193

190
M. Rudzki et al.
FEATURE ARTICLE
ganic layers were washed with aq NaHCO3 (2 mL) and brine
(2 mL), dried (MgSO4), and filtered. The corresponding arene 3 was
obtained in pure form after removal of the solvent by distillation
over a Vigreux column.
into the corresponding monodeuterated arenes in high
yields and good to excellent deuteration grades (Table 3,
entries 1–4). This method led to improved yields for com-
pound 3f compared to the copper system (entry 5). How-
ever, an exchange of one of the protons for deuterium in
33% of the methyl groups was observed for silver. Ben-
zothiophene (1b), which was deuterated regiospecifically
with the copper system, underwent detectable deuterium
scrambling when using the silver-based catalyst (entry 6).
Uncatalyzed Decarboxylative Deuteration; General Procedure
for Method C¢
A 20-mL crimp-cap vial was charged with the carboxylic acid 1
(1.00 mmol). NMP (2.0 mL) and D2O (370 mL, 20.3 mmol) were
added via syringe. The resulting mixture was stirred for 10 min at
110 °C under a constant flow of N2 to remove the water isoto-
pomers. Two further portions of D2O (370 mL, 20.3 mmol) were
added, each time followed by 10 min of purging. For the actual de-
carboxylative deuteration, the vessel was sealed, and the mixture
was heated to 170 °C for 16 h. It was then poured into H2O (2 mL)
and extracted repeatedly with Et2O (2-mL portions). The combined
organic layers were washed with aq NaHCO3 (2 mL) and brine
(2 mL), dried (MgSO4), and filtered. The corresponding arene 3 was
obtained in pure form after distilling off the solvents over a Vigreux
column.
In conclusion, monodeuterated arenes can be selectively
synthesized via deuterodecarboxylation of (hetero)aro-
matic carboxylic acids. This methodology has high poten-
tial for the selective deuterium-labeling of aromatic
compounds for biochemical or mechanistic investiga-
tions. Both copper- and silver-based catalyst systems are
suitable for this transformation and provide the desired
ipso-deuterated arenes in good to excellent yields and
deuteration grades. Remarkably, quinoline- and isoquino-
linecarboxylic acids gave monodeuterated heterocycles in
excellent yields in the absence of a metal catalyst. Deute-
rium scrambling was observed in the course of the copper-
catalyzed decarboxylation of indole-2-carboxylic acid
and the silver-catalyzed deuterodecarboxylation of ben-
zothiophene-2-carboxylic acid.
1H-Indole-2-d (3a) and 1H-Indole-3-d (3a¢)
3a: [CAS Reg. No. 3972-52-9]; 3a¢: [CAS Reg. No. 57754-36-6]
Following method A¢ from 1H-indole-2-carboxylic acid (1a,
173 mg, 1.00 mmol) gave 3a/3a¢ (64 mg, 54%) as an off-white sol-
id; ratio 3a/3a¢ 55:45 mixture; mp 49.3 °C.
Indole-2-d (3a)
1H NMR (400 MHz, CDCl3): d = 8.13 (br s, 1 H), 7.71 (m, 1 H),
7.41 (d, J = 8.1 Hz, 1 H), 7.25 (m, 1 H), 7.18 (m, 1 H), 6.61 (m, 1 H).
All reactions were carried out with deoxygenated solvents in oven-
dried glassware under an N2 atmosphere. NMP was dried by remov-
ing H2O as a toluene azeotrope. Quinoline was freshly distilled and
all inorganic bases were dried for 2 h in vacuo at r.t. prior to use.
The solvents were degassed using freeze-pump-thaw method. All
other compounds are commercially available and were used without
further purification. Mass spectral data were acquired on a GC-MS
Saturn 2100 T (Varian).
1
13C NMR (100 MHz, CDCl3): d = 135.7, 127.8, 123.9 (t, J = 28
Hz), 122.0, 120.7, 119.8, 110.0, 102.6.
2H NMR (60 MHz, CH2Cl2): d = 7.22 (s, 55%), 6.57 (s, 45%).
MS: m/z (%) = 119 (18), 118 (100), 117 (97), 91 (32), 90 (61), 89
(45), 63 (21).
Benzothiophene-2-d (3b)
[CAS Reg. No. 63724-94-7]
Copper-Catalyzed Decarboxylative Deuteration; General Pro-
cedure for Method A¢
Following method A¢ from benzothiophene-2-carboxylic acid (1b,
178 mg, 1.00 mmol) gave 3b (92 mg, 68%) as a colorless solid; mp
26.2 °C.
A 20-mL crimp-cap vial was charged with the carboxylic acid 1
(1.00 mmol), Cu2O (7.2 mg, 0.05 mmol), and 1,10-phenanthroline
(18 mg, 0.10 mmol). NMP (1.5 mL), quinoline (0.5 mL), and D2O
(370 mL, 20.3 mmol) were added via syringe. The resulting mixture
was stirred for 10 min at 110 °C under a constant flow of N2 to re-
move the water isotopomers. Two further portions of D2O (370 mL,
20.3 mmol) were added, each time followed by 10 min of purging.
For the actual decarboxylative deuteration, the vessel was sealed,
and the mixture was heated to 170 °C for 16 h. It was then poured
into aq 5 M HCl (2 mL) and extracted repeatedly with Et2O (2-mL
portions). The combined organic layers were washed with aq
NaHCO3 (2 mL) and brine (2 mL), dried (MgSO4), and filtered. The
corresponding arene 3 was obtained in pure form after distilling off
the solvents over a Vigreux column.
Following method B¢ yielded a mixture of benzothiophene-2-d (3b)
and benzothiophene-3-d (3b¢) [CAS Reg. No. 15816-45-2].
1H NMR (400 MHz, CDCl3): d = 7.94 (d, J = 7.5 Hz, 1 H), 7.87 (t,
J = 7.2 Hz, 1 H), 7.40 (m, 3 H).
13C NMR (100 MHz, CDCl3): d = 139.7, 139.6, 126.1 (t, J = 27
Hz), 124.2, 124.1, 123.7, 123.6, 122.7.
2H NMR (60 MHz, CHCl3): d = 7.52 (s, 1 D).
1
MS: m/z (%) = 136 (15), 135 (100), 134 (46), 91 (15), 90 (24), 69
(15), 63 (15).
Quinoline-2-d (3c)
[CAS Reg. No. 15793-81-4]
Silver-Catalyzed Decarboxylative Deuteration; General Proce-
dure for Method B¢
Following method C¢ from quinoline-2-carboxylic acid (1c,
173 mg, 1.00 mmol) gave 3c (113 mg, 87%) as a colorless liquid.
1H NMR (400 MHz, CDCl3): d = 8.13 (m, 2 H), 7.82 (d, J = 8.2 Hz,
1 H), 7.73 (t, J = 7.0 Hz, 1 H), 7.56 (t, J = 7.0 Hz, 1 H), 7.40 (d,
J = 8.2 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 149.8 (t, J = 27 Hz), 148.1,
136.0, 129.3, 129.2, 128.3, 127.7, 126.4, 120.9.
A Schlenk tube was charged with the carboxylic acid 1
(1.00 mmol). D2O (2 mL, 110 mmol) was added via syringe, and
the resulting mixture was stirred at 100 °C for 15 min, and the D2O/
HDO mixture was removed in vacuo. For the actual carboxylative
deuteration, NMP (2 mL) was added via syringe, and the resulting
soln was added to a reaction vessel charged with AgOAc (17.2 mg,
0.10 mmol) and K2CO3 (20.0 mg, 0.15 mmol). The resulting mix-
ture was stirred at 120 °C for 16 h. Then, it was allowed to cool to
r.t., diluted with Et2O (2 mL), poured into aq 5 M HCl (2 mL), and
extracted repeatedly with Et2O (2-mL portions). The combined or-
1
2H NMR (60 MHz, CHCl3): d = 8.92 (s, 1 D).
MS: m/z (%) = 130 (100), 103 (25), 76 (15), 63 (10), 50 (15), 40 (3).
Synthesis 2012, 44, 184–193
© Thieme Stuttgart · New York

FEATURE ARTICLE
Copper- or Silver-Catalyzed Decarboxylative Deuteration of Aromatic Carboxylic Acids
191
Isoquinoline-1-d (3d)
[CAS Reg. No. 15793-88-1]
IR: 3405 (s), 3383 (s), 3035 (m), 1594 (vs), 1518 (vs), 1495 (s),
1415 (s), 1321 (vs), 1172 (m), 881 (s), 748 (vs), 700 (m), 690 (vs),
627 cm–1 (s).
1H NMR (400 MHz, CDCl3): d = 7.30 (t, J = 7.5 Hz, 4 H), 7.11 (d,
J = 7.5 Hz, 3 H), 6.96 (t, J = 6.5 Hz, 2 H), 5.73 (s, 1 H).
Following method C¢ from isoquinoline-1-carboxylic acid (1d,
173 mg, 1.00 mmol) gave 3d (115 mg, 88%) as a colorless solid.
1H NMR (400 MHz, CDCl3): d = 8.53 (d, J = 4.0 Hz, 1 H), 7.97 (d,
J = 8.0 Hz, 1 H), 7.82 (d, J = 8.0 Hz, 1 H), 7.69 (m, 1 H), 7.66 (d,
J = 4.0 Hz, 1 H), 7.60 (m, 1 H).
13C NMR (150 MHz, CDCl3): d = 143.0, 129.3, 129.2, 121.0, 120.9,
117.8, 117.2 (t, 1J = 24 Hz).
1
13C NMR (100 MHz, CDCl3): d = 151.9 (t, J = 27 Hz), 142.7,
2H NMR (60 MHz, acetone): d = 7.19 (s, 1 D).
135.7, 130.3, 128.5, 127.5, 127.2, 126.4, 120.5.
MS: m/z (%) = 171 (18), 170 (81), 169 (100), 168 (60), 167 (26), 51
(26), 50 (17).
2H NMR (60 MHz, CHCl3): d = 9.23 (s, 1 D).
MS: m/z (%) = 130 (100), 103 (30), 76 (15), 63 (10), 50 (15), 40 (5).
GC/HRMS (EI): m/z [M+] calcd for C12H10DN: 170.0954; found:
170.0963.
2-Nitrobenzene-d (3e)
[CAS Reg. No. 32488-51-0]
Benzonitrile-4-d (3i)
[CAS Reg. No. 13122-35-5]
Following method A¢ from 2-nitrobenzoic acid (1e, 167 mg,
1.00 mmol) gave 3e (89 mg, 72%) as a yellow liquid.
1H NMR (400 MHz, CDCl3): d = 8.23 (d, J = 8.0 Hz, 1 H), 7.71 (t,
J = 8.0 Hz, 1 H), 7.54–7.57 (m, 2 H).
Following method A¢ from 4-cyanobenzoic acid (1i, 147 mg,
1.00 mmol) using 4,7-diphenyl-1,10-phenanthroline as the ligand
gave 3i (57 mg, 58%) as a colorless liquid.
1H NMR (400 MHz, CDCl3): d = 7.57–7.64 (m, 2 H), 7.43–7.47 (m,
2 H).
13C NMR (100 MHz, CDCl3): d = 132.2 (t, J = 26 Hz), 132.0,
128.8, 118.7, 112.3.
2H NMR (60 MHz, CHCl3): d = 7.29 (s, 1 D).
13C NMR (150 MHz, CDCl3): d = 148.0, 134.5, 129.2, 129.1, 123.1
(t, 1J = 26 Hz).
1
2H NMR (60 MHz, CHCl3): d = 8.27 (s, 1 D).
MS: m/z (%) = 123 (45), 93 (30), 77 (100), 65 (25), 51 (70).
Methyl Phenyl-2-d Sulfone (3f)
MS: m/z (%) = 104 (100), 76 (60), 63 (10), 50 (50).
Following method A¢ from 2-(methylsulfonyl)benzoic acid (1f,
200 mg, 1.00 mmol) gave 3f (79 mg, 50%) as a white solid; mp 88.1
°C.
5-Methoxy-2-nitrobenzene-d (3j)
Following method B¢ from 5-methoxy-2-nitrobenzoic acid (1j,
197 mg, 1.00 mmol) gave 3j (150 mg, 97%) as an off-white solid;
mp 51.2 °C).
Following method B¢ gave 3f/3f¢ (147 mg, 94%); ratio 3f/3f¢ 65:33.
IR: 3021 (s), 3008 (s), 2927 (s), 1583 (w), 1419 (s), 1448 (s), 1328
(s), 1288 (vs), 1228 (s), 1147 (vs), 1085 (s), 966 (s), 775 (s), 750
(m), 688 cm–1 (s).
IR: 3117 (m), 2976 (m), 2939 (m), 1601 (s), 1587 (vs), 1497 (vs),
1483 (vs), 1457 (s), 1339 (vs), 1330 (vs), 1250 (vs), 1240 cm–1 (vs).
1H NMR (400 MHz, CDCl3): d = 7.96 (d, J = 7.4 Hz, 1 H), 7.67 (m,
1 H), 7.59 (m, 2 H), 3.06 (s, 3 H).
1H NMR (400 MHz, CDCl3): d = 8.22 (d, J = 9.9 Hz, 1 H), 6.98 (m,
2 H), 3.93 (s, 3 H).
13C NMR (150 MHz, CDCl3): d = 140.5, 133.7, 129.4, 129.3, 127.1
13C NMR (150 MHz, CDCl3): d = 164.6, 141.5, 125.9, 125.7 (t,
(t, 1J = 25 Hz), 44.5.
1J = 25 Hz), 114.0, 113.9, 56.0.
2H NMR (60 MHz, CHCl3): d = 7.62 (s, 1 D).
2H NMR (60 MHz, CHCl3): d = 8.26 (s, 1 D).
GC/HRMS (EI): m/z [M+] calcd for C7H6DNO3: 154.0473; found:
MS: m/z (%) = 142 (33), 95 (68), 94 (49), 78 (100), 77 (74), 51 (55),
50 (33).
154.0475.
GC/HRMS (EI): m/z [M+] calcd for C7H7DO2S: 157.0308; found:
157.0308.
2,6-Dimethoxybenzene-d (3k)
[CAS Reg. No. 49771-99-5]
Benzophenone-2-d (3g)
[CAS Reg. No. 72302-35-3]
Following method B¢ from 2,6-dimethoxybenzoic acid (1k,
187 mg, 1.00 mmol) gave 3k (106 mg, 77%) as a yellow liquid.
Following method A¢ from 2-benzoylbenzoic acid (1g, 226 mg,
1.00 mmol) gave 3g (140 mg, 77%) as a colorless solid; mp 48.0 °C.
1H NMR (400 MHz, CDCl3): d = 7.20 (t, J = 8.0 Hz, 1 H), 6.52 (d,
J = 8.0 Hz, 2 H), 3.80 (s, 6 H).
1H NMR (400 MHz, CDCl3): d = 7.82 (d, J = 7.4 Hz, 3 H), 7.60 (t,
J = 7.4 Hz, 2 H), 7.50 (m, 4 H).
13C NMR (150 MHz, CDCl3): d = 160.9, 129.9, 106.2, 100.2 (t,
1J = 24 Hz), 55.3.
13C NMR (100 MHz, CDCl3): d = 196.8, 137.6, 137.5, 132.4, 129.8
2H NMR (60 MHz, CHCl3): d = 6.53 (s, 1 D).
(t, 1J = 24 Hz), 128.3, 128.2.
MS: m/z (%) = 140 (19), 139 (100), 138 (8), 110 (29), 109 (6), 96
(12), 64 (11).
2H NMR (60 MHz, CHCl3): d = 7.87 (s, 1 D).
MS: m/z (%) = 184 (48), 183 (67), 182 (24), 106 (63), 105 (100), 77
(15), 51 (14).
2,4,6-Trichlorobenzene-d (3l)
[CAS Reg. No. 16463-22-2]
N-Phenylbenzen-2-d-amine (3h)
Following method B¢ from 2,4,6-trichlorobenzoic acid (1l, 225 mg,
1.00 mmol) gave 3l (130 mg, 71%) as a white solid; mp 62.9 °C.
1H NMR (400 MHz, CDCl3): d = 7.29 (s, 2 H).
Following method A¢ from 2-(phenylamino)benzoic acid (1h,
215 mg, 1.00 mmol) gave 3h (109 mg, 64%) as a colorless solid;
mp 54.1 °C.
13C NMR (100 MHz, CDCl3): d = 135.5, 135.4, 127.2, 126.9 (t,
1J = 24 Hz).
© Thieme Stuttgart · New York
Synthesis 2012, 44, 184–193

192
M. Rudzki et al.
FEATURE ARTICLE
Gooßen, L. J. Adv. Synth. Catal. 2011, 353, 337.
(c) Gooßen, L. J.; Rudolphi, F.; Oppel, C.; Rodríguez, N.
Angew. Chem. Int. Ed. 2008, 47, 3043.
2H NMR (60 MHz, acetone): d = 7.51 (s, 1 D).
MS: m/z (%) = 185 (58), 184 (94), 183 (100), 182 (68), 147 (45), 76
(38), 75 (41).
(10) (a) Voutchkova, A.; Coplin, A.; Leadbeater, N. E.; Crabtree,
R. H. Chem. Commun. 2008, 47, 6312. (b) Wang, C. Y.;
Piel, I.; Glorius, F. J. Am. Chem. Soc. 2009, 131, 4194.
(c) Wang, C.; Rakshit, S.; Glorius, F. J. Am. Chem. Soc.
2010, 132, 14006. (d) Cornella, J.; Lu, P.; Larrosa, I. Org.
Lett. 2009, 11, 5506. (e) Zhang, F.; Greaney, M. F. Angew.
Chem. Int. Ed. 2010, 49, 2768. (f) Fang, P.; Li, M.; Ge, H.
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Lett. 2010, 12, 3464. (h) Wie, J.; Jiao, N. Org. Lett. 2010,
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Chem. Eur. J. 2009, 15, 3666.
2-Bromo-4,5-dimethoxybenzene-d (3m)
Following method B¢ from 2-bromo-4,5-dimethoxybenzoic acid
(1m, 269 mg, 1.00 mmol) gave 3m (163 mg, 75%) as a colorless
liquid.
IR: 3001 (vs), 2957 (vs), 2939 (vs), 2905 (vs), 2837 (vs), 1583 (s),
1493 (vs), 1461 (s), 1435 (s), 1361 (s), 1254 (vs), 1214 (s), 1026 (s),
836 cm–1 (m).
1H NMR (400 MHz, CDCl3): d = 6.98 (s, 1 H), 6.74 (s, 1 H), 3.87
(s, 3 H), 3.86 (s, 3 H).
(11) (a) Hu, P.; Kan, J.; Su, W. P.; Hong, M. C. Org. Lett. 2009,
11, 2341. (b) Fu, Z. J.; Huang, S. J.; Su, W.; Hong, M. Org.
Lett. 2010, 12, 4992. (c) Sun, Z.-M.; Zhang, J.; Zhao, P.
Org. Lett. 2010, 12, 992. (d) Tanaka, D.; Romeril, S. P.;
Myers, A. G. J. Am. Chem. Soc. 2005, 127, 10323.
(e) Zhang, S. L.; Fu, Y.; Shang, R.; Guo, Q. X.; Liu, L. J. Am.
Chem. Soc. 2010, 132, 638.
1
13C NMR (100 MHz, CDCl3): d = 149.7, 148.3, 123.1 (t, J = 26
Hz), 114.8, 112.6, 112.4, 56.1, 56.0.
2H NMR (60 MHz, acetone): d = 7.06 (s, 1 D).
GC/HRMS (EI): m/z [M+] calcd for C8H8DBrO2: 218.9849; found:
218.9856.
(12) Smith, M. B.; March, J. In Advanced Organic Chemistry,
5th ed.; Wiley: New York, 2001, 732.
(13) For a review on removable directing groups see: Rousseau,
G.; Breit, B. Angew. Chem. Int. Ed. 2011, 50, 2450.
(14) Noland, W. E.; Baude, F. J. Org. Synth. Coll. Vol. V; John
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(15) Hantzsch, A. Ber. Dtsch. Chem. Ges. 1881, 14, 1637.
(16) (a) Maehara, A.; Tsurugi, H.; Satoh, T.; Miura, M. Org. Lett.
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Acknowledgment
We thank C. Oppel for helpful discussions and Nanokat, the DFG
(SFB/TRR 88 3MET), the A. v. Humboldt foundation (fellowships
to N.R. and W.I.D.), and the Deutsche Bundesstiftung Umwelt (fel-
lowship to M.R.) for financial support.
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